Sex differences in attention-deficit hyperactivity disorder diagnosis and clinical care: a national study of population healthcare records in Wales.

BACKGROUND: Population-based studies have observed sex biases in the diagnosis and treatment of attention-deficit hyperactivity disorder (ADHD). Females are less likely to be diagnosed or prescribed ADHD medication. This study uses national healthcare records, to investigate sex differences in diagnosis and clinical care in young people with ADHD, particularly regarding recognition and treatment of other mental health conditions. METHODS: The cohort included individuals diagnosed with ADHD, born between 1989 and 2013 and living in Wales between 2000 and 2019. Routine primary and secondary healthcare record data were used to derive diagnoses of ADHD and other neurodevelopmental and mental health conditions, as well as ADHD and antidepressant medications. Demographic variables included ethnicity, socioeconomic deprivation and contact with social services. RESULTS: There were 16,458 individuals diagnosed with ADHD (20.3% females, ages 3-30 years), with a male-to-female ratio of 3.9:1. Higher ratios (4.8:1) were seen in individuals diagnosed younger (<12 years), with the lowest ratio (1.9:1) in those diagnosed as adults (>18). Males were younger at first recorded ADHD diagnosis (mean = 10.9 vs. 12.6 years), more likely to be prescribed ADHD medication and younger at diagnosis of co-occurring neurodevelopmental conditions. In contrast, females were more likely to receive a diagnosis of anxiety, depression or another mental health condition and to be prescribed antidepressant medications, prior to ADHD diagnosis. These sex differences were largely stable across demographic groups. CONCLUSIONS: This study adds to the evidence base that females with ADHD are experiencing later recognition and treatment of ADHD. The results indicate that this may be partly because of diagnostic overshadowing from other mental health conditions, such as anxiety and depression, or initial misdiagnosis. Further research and dissemination of findings to the public are needed to improve awareness, timely diagnosis and treatment of ADHD in females.

Correlation vs. exchange competition drives the singlet-triplet excited-state inversion in non-alternant hydrocarbons.

In this work, we focus on the understanding of the driving force behind the S1-T1 excited-state energy inversion (which would thus violate Hund's rule, making the S1 state lower in energy than the T1 state) of two non-benzenoid non-alternant hydrocarbons, composed of odd-membered rings. The molecules considered here have identical chemical composition but different atomic configuration in space. The delicate interplay between structural and electronic factors that might induce inversion and its energy extension, only by a few meV, is systematically investigated here by state-of-the-art calculations. Qualitative and quantitative accurate predictions are obtained employing post-HF methods, thanks to the balanced and careful inclusion of electron correlation effects. The obtained results might guide and rationalize new searches for molecules violating Hund's rule, concomitantly demonstrating the importance of key contributions from the theoretical method of choice.

Violation of Hund's rule in molecules: Predicting the excited-state energy inversion by TD-DFT with double-hybrid methods.

The energy difference (ΔEST) between the lowest singlet (S1) state and the triplet (T1) excited state of a set of azaphenalene compounds, which is theoretically and experimentally known to violate Hund's rule, giving rise to the inversion of the order of those states, is calculated here with a family of double-hybrid density functionals. That excited-state inversion is known to be very challenging to reproduce for time-dependent density functional theory employing common functionals, e.g., hybrid or range-separated expressions, but not for wavefunction methods due to the inclusion of higher-than-single excitations. Therefore, we explore here if the last developed family of density functional expressions (i.e., double-hybrid models) is able to provide not only the right excited-state energy order but also accurate ΔEST values, thanks to the approximate inclusion of double excitations within these models. We herein employ standard double-hybrid (B2-PLYP, PBE-QIDH, and PBE0-2), range-separated (ωB2-PLYP and RSX-QIDH), spin-scaled (SCS/SOS-B2PLYP21, SCS-PBE-QIDH, and SOS-PBE-QIDH), and range-separated spin-scaled (SCS/SOS-ωB2-PLYP, SCS-RSX-QIDH, and SOS-RSX-QIDH) expressions to systematically assess the influence of the ingredients entering into the formulation while concomitantly providing insights for their accuracy.

Singlet-Triplet Excited-State Inversion in Heptazine and Related Molecules: Assessment of TD-DFT and ab initio Methods.

We have investigated the origin of the S1 -T1 energy levels inversion for heptazine, and other N-doped π-conjugated hydrocarbons, leading thus to an unusually negative singlet-triplet energy gap ( ΔEST<0 ). Since this inversion might rely on substantial doubly-excited configurations to the S1 and/or T1 wavefunctions, we have systematically applied multi-configurational SA-CASSCF and SC-NEVPT2 methods, SCS-corrected CC2 and ADC(2) approaches, and linear-response TD-DFT, to analyze if the latter method could also face this challenging issue. We have also extended the study to B-doped π-conjugated systems, to see the effect of chemical composition on the results. For all the systems studied, an intricate interplay between the singlet-triplet exchange interaction, the influence of doubly-excited configurations, and the impact of dynamic correlation effects, serves to explain the ΔEST<0 values found for most of the compounds, which is not predicted by TD-DFT.

peri-Acenoacene molecules: tuning of the singlet and triplet excitation energies by modifying their radical character.

The energy difference between singlet and triplet excitons, or ΔEST, is a key parameter for novel light-emission mechanisms (i.e., TADF or thermally activated delayed fluorescence) or other photoactivated processes. We have studied a set of conjugated molecules (peri-acenoacenes and their heteroatom-doped analogues) to observe the evolution of their excited-state properties upon increasing the system size with and without substitution with a pair of N atoms. Since these molecules exhibit a (ground-state) diradicaloid character, together with marked correlation effects influencing the excited-states formed, we have applied a variety of theoretical methods (FT-DFT, TD-DFT, SF-TD-DFT, CIS, CIS(D), SCS-CC2, SA-CASSCF, and SC-NEVPT2) to bracket the accuracy of the results while concomitantly providing insights into electronic structure. The results show how this chemical strategy (N-doping) largely modifies not only the excited-state energies but also the oscillator strengths and the ΔEST values, constituting versatile platforms for fine-tuned photophysical applications.

Negative Singlet-Triplet Excitation Energy Gap in Triangle-Shaped Molecular Emitters for Efficient Triplet Harvesting.

The full harvesting of both singlet and triplet excitons can pave the way toward more efficient molecular light-emission mechanisms (i.e., TADF or thermally activated delayed fluorescence) beyond the spin statistics limit. This TADF mechanism benefits from low (but typically positive) singlet-triplet energy gaps or ΔEST. Recent research has suggested the possibility of inverting the order of the energy of lowest singlet and triplet excited states, thus opening new pathways to promote light emission without any energy barrier through triplet to singlet conversion, which is systematically investigated here by means of theoretical methods. To this end, we have selected a set of heteroatom-substituted triangle-shaped molecules (or triangulenes) for which ΔEST < 0 is predicted. We successfully rationalize the origin of that energy inversion and the reasons for which theoretical methods might produce qualitatively inconsistent predictions depending on how they treat n-tuple excitations (e.g., the large contribution of double excitations for all of the ground and excited states involved). Unfortunately, the time-dependent density functional theory method is unable to deal with the physical effects driving this behavior, which prompted us to use more sophisticated ab initio methods here such as SA-CASSCF, SC-NEVPT2, SCS-CC2, and SCS-ADC(2).

The positive association between perceived parental responsiveness and self-esteem, anxiety, and thriving among youth rugby players: A multigroup analysis.

The purpose of this study was to examine the association between young players' perception of mother's and father's responsiveness with their self-esteem, anxiety (i.e., worry), and thriving (i.e., positive affect, vitality, and life satisfaction). In total, 314 male British rugby players with a mean age of 16.23 years (SD = 0.26) completed the study in two phases: n = 124 (first dataset), and n = 192 (second dataset). Participants trained on average 3.14 times/week (SD = 0.94) and had been involved in rugby for an average of 8.21 years (SD = 2.89). Participants completed questionnaires measuring perceived parental responsiveness (PPR) for their mother and father, self-esteem, worry about sport performance, and thriving indicators (i.e., positive affect, vitality, and life satisfaction). The results consistently indicated that participants' perceptions of their mother's and father's responsiveness positively related to thriving, and negatively related to their worry about sport performance, mediated by their self-esteem. Overall, the study highlights the need for parents to be provided with insights into the value of being responsive to their child and being encouraged to regularly talk with their child regarding their needs and desires, and seeking to understand how their child perceives the support they currently receive.

Quality of Recovery, Postdischarge Hospital Utilization, and 2-Year Functional Outcomes After an Outpatient Total Knee Arthroplasty Program.

BACKGROUND: Outpatient total knee arthroplasty (TKA) has been made possible with advances in perioperative care and standardized clinical inpatient pathways. While many studies report on benefits of outpatient programs, none explore patient-reported outcome measures. As such, our goals were to compare the short-term quality of recovery; highlight postdischarge hospital resources utilization; and report on 2-year functional outcomes scores. METHODS: This was a prospective comparative cohort study of 43 inpatients (43 TKAs) and 43 outpatients (43 TKAs) operated on by a single surgeon between September 28, 2010 and May 5, 2015. All patients were given a diary to complete at 1, 3, 7, 14, and 28 days postoperatively; we collected 90-day complications, readmissions, and emergency department visits; Knee Injury and Osteoarthritis Outcome Score and Western Ontario and McMaster Universities Osteoarthritis Index scores were completed preoperatively and 2 years postoperatively. SPSS (IBM, version 22.0) was used for all statistical analyses. RESULTS: Quality of recovery (QoR-9) was similar in the outpatient TKA group compared with the inpatient group. No statistically significant differences were observed for Knee Injury and Osteoarthritis Outcome Score and Western Ontario and McMaster Universities Osteoarthritis Index subscores (P > .05). There was 1 readmission in both outpatient and inpatient groups. Six inpatients and 8 outpatients returned to the emergency department for any reason within 90 days, with no statistical significance observed between the 2 groups (P = .771). CONCLUSION: Outpatient TKA in selected patients produced similar short-term and 2-year patient-reported outcome measures and a comparable 90-day postdischarge hospital resource utilization when compared to an inpatient cohort, supporting further investigation into outpatient TKA.

Estimation of π-π Electronic Couplings from Current Measurements.

The π-π interactions between organic molecules are among the most important parameters for optimizing the transport and optical properties of organic transistors, light-emitting diodes, and (bio-) molecular devices. Despite substantial theoretical progress, direct experimental measurement of the π-π electronic coupling energy parameter t has remained an old challenge due to molecular structural variability and the large number of parameters that affect the charge transport. Here, we propose a study of π-π interactions from electrochemical and current measurements on a large array of ferrocene-thiolated gold nanocrystals. We confirm the theoretical prediction that t can be assessed from a statistical analysis of current histograms. The extracted value of t ≈35 meV is in the expected range based on our density functional theory analysis. Furthermore, the t distribution is not necessarily Gaussian and could be used as an ultrasensitive technique to assess intermolecular distance fluctuation at the subangström level. The present work establishes a direct bridge between quantum chemistry, electrochemistry, organic electronics, and mesoscopic physics, all of which were used to discuss results and perspectives in a quantitative manner.

Electrochemical Genetic Profiling of Single Cancer Cells.

Recent understandings in the development and spread of cancer have led to the realization of novel single cell analysis platforms focused on circulating tumor cells (CTCs). A simple, rapid, and inexpensive analytical platform capable of providing genetic information on these rare cells is highly desirable to support clinicians and researchers alike to either support the selection or adjustment of therapy or provide fundamental insights into cell function and cancer progression mechanisms. We report on the genetic profiling of single cancer cells, exploiting a combination of multiplex ligation-dependent probe amplification (MLPA) and electrochemical detection. Cells were isolated using laser capture and lysed, and the mRNA was extracted and transcribed into DNA. Seven markers were amplified by MLPA, which allows for the simultaneous amplification of multiple targets with a single primer pair, using MLPA probes containing unique barcode sequences. Capture probes complementary to each of these barcode sequences were immobilized on a printed circuit board (PCB) manufactured electrode array and exposed to single-stranded MLPA products and subsequently to a single stranded DNA reporter probe bearing a HRP molecule, followed by substrate addition and fast electrochemical pulse amperometric detection. We present a simple, rapid, flexible, and inexpensive approach for the simultaneous quantification of multiple breast cancer related mRNA markers, with single tumor cell sensitivity.

New Insights in Thrombin Inhibition Structure-Activity Relationships by Characterization of Octadecasaccharides from Low Molecular Weight Heparin.

Low Molecular Weight Heparins (LMWH) are complex anticoagulant drugs that mainly inhibit the blood coagulation cascade through indirect interaction with antithrombin. While inhibition of the factor Xa is well described, little is known about the polysaccharide structure inhibiting thrombin. In fact, a minimal chain length of 18 saccharides units, including an antithrombin (AT) binding pentasaccharide, is mandatory to form the active ternary complex for LMWH obtained by alkaline ß-elimination (e.g., enoxaparin). However, the relationship between structure of octadecasaccharides and their thrombin inhibition has not been yet assessed on natural compounds due to technical hurdles to isolate sufficiently pure material. We report the preparation of five octadecasaccharides by using orthogonal separation methods including size exclusion, AT affinity, ion pairing and strong anion exchange chromatography. Each of these octadecasaccharides possesses two AT binding pentasaccharide sequences located at various positions. After structural elucidation using enzymatic sequencing and NMR, in vitro aFXa and aFIIa were determined. The biological activities reveal the critical role of each pentasaccharide sequence position within the octadecasaccharides and structural requirements to inhibit thrombin. Significant differences in potency, such as the twenty-fold magnitude difference observed between two regioisomers, further highlights the importance of depolymerisation process conditions on LMWH biological activity.

Determining the cohesive energy of coronene by dispersion-corrected DFT methods: periodic boundary conditions vs. molecular pairs.

We investigate the cohesive energy of crystalline coronene by the dispersion-corrected methods DFT-D2, DFT-D3, and DFT-NL. For that purpose, we first employ bulk periodic boundary conditions and carefully analyze next all the interacting pairs of molecules within the crystalline structure. Our calculations reveal the nature and importance of the binding forces in every molecular pair tackled and provide revised estimates of the effects of two- and three-body terms, leading to accurate results in close agreement with experimental (sublimation enthalpies) reference values.

Different effects of whole-cell and acellular vaccines on Bordetella transmission.

BACKGROUND: Vaccine development has largely focused on the ability of vaccines to reduce disease in individual hosts, with less attention to assessing the vaccine's effects on transmission between hosts. Current acellular vaccines against Bordetella pertussis are effective in preventing severe disease but have little effect on less severe coughing illness that can mediate transmission. METHODS: Using mice that are natural host's of Bordetella bronchiseptica, we determined the effects of vaccination on shedding and transmission of this pathogen. RESULTS: Vaccination with heat-killed whole-cell B. bronchiseptica or B. pertussis inhibited shedding of B. bronchiseptica. Differences in neutrophil and B-cell recruitment distinguished sham-vaccine from whole-cell-----vaccine responses and correlated with shedding output. Both B and T cells were essential for vaccine-induced control of shedding. Adoptive transfer of antibodies was able to limit shedding, while depletion of CD4(+) T cells led to increased shedding in vaccinated mice. Finally, whole-cell vaccination was able to prevent transmission, but an acellular vaccine that effectively controls disease failed to control shedding and transmission. CONCLUSIONS: Our results highlight discrepancies between whole-cell and acellular vaccination that could contribute to the increased incidence of B. pertussis infection since the transition to the use of acellular vaccination.

Resident microbiota affect Bordetella pertussis infectious dose and host specificity.

Before contacting host tissues, invading pathogens directly or indirectly interact with host microbiota, but the effects of such interactions on the initial stages of infection are poorly understood. Bordetella pertussis is highly infectious among humans but requires large doses to colonize rodents, unlike a closely related zoonotic pathogen, Bordetella bronchiseptica, raising important questions about the contributions of bacterial competition to initial colonization and host selection. We observed that <100 colony-forming units (CFU) of B. bronchiseptica efficiently infected mice and displaced culturable host microbiota, whereas 10 000 CFU of B. pertussis were required to colonize murine nasal cavities and did not displace host microorganisms. Bacteria isolated from murine nasal cavities but not those from the human lower respiratory tract limited B. pertussis growth in vitro, indicating that interspecies competition may limit B. pertussis colonization of mice. Further, a broad-spectrum antibiotic treatment delivered before B. pertussis inoculation reduced the infectious dose to <100 CFU, and reintroduction of single Staphylococcus or Klebsiella species was sufficient to inhibit B. pertussis colonization of antibiotic-treated mice. Together, these results reveal that resident microorganisms can prevent B. pertussis colonization and influence host specificity, and they provide rationale for manipulating microbiomes to create more-accurate animal models of infectious diseases.

Exploring the energy landscape of the charge transport levels in organic semiconductors at the molecular scale.

The extraordinary semiconducting properties of conjugated organic materials continue to attract attention across disciplines including materials science, engineering, chemistry, and physics, particularly with application to organic electronics. Such materials are used as active components in light-emitting diodes, field-effect transistors, or photovoltaic cells, as a substitute for (mostly Si-based) inorganic semiconducting materials. Many strategies developed for inorganic semiconductor device building (doping, p-n junctions, etc.) have been attempted, often successfully, with organics, even though the key electronic and photophysical properties of organic thin films are fundamentally different from those of their bulk inorganic counterparts. In particular, organic materials consist of individual units (molecules or conjugated segments) that are coupled by weak intermolecular forces. The flexibility of organic synthesis has allowed the development of more efficient opto-electronic devices including impressive improvements in quantum yields for charge generation in organic solar cells and in light emission in electroluminescent displays. Nonetheless, a number of fundamental questions regarding the working principles of these devices remain that preclude their full optimization. For example, the role of intermolecular interactions in driving the geometric and electronic structures of solid-state conjugated materials, though ubiquitous in organic electronic devices, has long been overlooked, especially when it comes to these interfaces with other (in)organic materials or metals. Because they are soft and in most cases disordered, conjugated organic materials support localized electrons or holes associated with local geometric distortions, also known as polarons, as primary charge carriers. The spatial localization of excess charges in organics together with low dielectric constant (ε) entails very large electrostatic effects. It is therefore not obvious how these strongly interacting electron-hole pairs can potentially escape from their Coulomb well, a process that is at the heart of photoconversion or molecular doping. Yet they do, with near-quantitative yield in some cases. Limited screening by the low dielectric medium in organic materials leads to subtle static and dynamic electronic polarization effects that strongly impact the energy landscape for charges, which offers a rationale for this apparent inconsistency. In this Account, we use different theoretical approaches to predict the energy landscape of charge carriers at the molecular level and review a few case studies highlighting the role of electrostatic interactions in conjugated organic molecules. We describe the pros and cons of different theoretical approaches that provide access to the energy landscape defining the motion of charge carriers. We illustrate the applications of these approaches through selected examples involving OFETs, OLEDs, and solar cells. The three selected examples collectively show that energetic disorder governs device performances and highlights the relevance of theoretical tools to probe energy landscapes in molecular assemblies.

Isolation of a pure octadecasaccharide with antithrombin activity from an ultra-low-molecular-weight heparin.

Heparin and low-molecular-weight heparins (LMWHs) are anticoagulant drugs that mainly inhibit the coagulation cascade by indirectly interacting with factor Xa and factor IIa (thrombin). Inhibition of factor Xa by antithrombin (AT) requires the activation of AT by specific pentasaccharide sequences containing 3-O-sulfated glucosamine. Activated AT also inhibits thrombin by forming a stable ternary complex of AT, thrombin, and a polysaccharide (requires at least an 18-mer/octadeca-mer polysaccharide). The full structure of any naturally occurring octadecasaccharide sequence has yet to be determined. In the context of the development of LMWH biosimilars, structural data on such important biological mediators could be helpful for better understanding and regulatory handling of these drugs. Here we present the isolation and identification of an octadecasaccharide with very high anti-factor Xa activity (∼3 times higher than USP [U.S. Pharmacopeia] heparin). The octadecasaccharide was purified using five sequential chromatographic methods with orthogonal specificity, including gel permeation, AT affinity, strong anion exchange, and ion-pair chromatography. The structure of the octadecasaccharide was determined by controlled enzymatic sequencing and nuclear magnetic resonance (NMR). The isolated octadecasaccharide contained three consecutive AT-binding sites and was tested in coagulation assays to determine its biological activity. The isolation of this octadecasaccharide provides new insights into the modulation of thrombin activity.

Understanding parental secure base support across youth sport contexts in Sweden.

The notion of secure base explains how a child can grow and become independent through access to a significant other (i.e., parent) who is available, encouraging, and noninterfering. The purpose of the current study was to develop an understanding of parental secure base support within the context of youth sport in Sweden, with a specific focus on: (a) what parental behaviors constitute a secure base, and (b) how these behaviors differ across contexts (at home before and after sport, at practice and during competitions). An interpretive descriptive methodology (Thorne, 2016) was used. Interviews were conducted with 13 family triads (children aged 12-15 years) and 1 dyad living in Sweden. Analysis was conducted to illuminate associations, patterns, and relationships within the sample. Analysis led to the development of nine categories of parental behaviors that were perceived to underpin a secure base. Availability was seen to comprise physical presence and support provision, being responsive, and developing positive mental representations. Encouragement encompassed demonstrating that sport participation is valued, motivating to explore sporting endeavors, and reinforcing and rewarding persistence in sports. Interference was described as unrequested interference, requested interference, and intentionally constrained involvement. Additionally, influencing factors such as communication, family structure and culture, were identified. The findings provide an empirical illustration for several behaviors that have been perceived as positive in previous literature, as well as highlighting numerous further complexities, particularly as it relates to interference.

Contacts with primary and secondary healthcare before suicide by those under the care of mental health services: case-control, whole-population-based study using person-level linked routine data in Wales, UK during 2000-2015.

BACKGROUND: People under the care of mental health services are at increased risk of suicide. Existing studies are small in scale and lack comparisons. AIMS: To identify opportunities for suicide prevention and underpinning data enhancement in people with recent contact with mental health services. METHOD: This population-based study includes people who died by suicide in the year following a mental health services contact in Wales, 2001-2015 (cases), paired with similar patients who did not die by suicide (controls). We linked the National Confidential Inquiry into Suicide and Safety in Mental Health and the Suicide Information Database - Cymru with primary and secondary healthcare records. We present results of conditional logistic regression. RESULTS: We matched 1031 cases with 5155 controls. In the year before their death, 98.3% of cases were in contact with healthcare services, and 28.5% presented with self-harm. Cases had more emergency department contacts (odds ratio 2.4, 95% CI 2.1-2.7) and emergency hospital admissions (odds ratio 1.5, 95% CI 1.4-1.7), but fewer primary care contacts (odds ratio 0.7, 95% CI 0.6-0.9) and out-patient appointments (odds ratio 0.2, 95% CI 0.2-0.3) than controls. Odds ratios were larger in females than males for injury and poisoning (odds ratio: 3.3 (95% CI 2.5-4.5) v. 2.6 (95% CI 2.1-3.1)). CONCLUSIONS: We may be missing existing opportunities to intervene, particularly in emergency departments and hospital admissions with self-harm presentations and with unattributed self-harm, especially in females. Prevention efforts should focus on strengthening routine care contacts, responding to emergency contacts and better self-harm care. There are benefits to enhancing clinical audit systems with routinely collected data.

Charge-transfer excitations steer the Davydov splitting and mediate singlet exciton fission in pentacene.

Quantum-chemical calculations are combined to a model Frenkel-Holstein Hamiltonian to assess the nature of the lowest electronic excitations in the pentacene crystal. We show that an admixture of charge-transfer excitations into the lowest singlet excited states form the origin of the Davydov splitting and mediate instantaneous singlet exciton fission by direct optical excitation of coherently coupled single and double exciton states, in agreement with recent experiments.

Obtaining the lattice energy of the anthracene crystal by modern yet affordable first-principles methods.

The non-covalent interactions in organic molecules are known to drive their self-assembly to form molecular crystals. We compare, in the case of anthracene and against experimental (electronic-only) sublimation energy, how modern quantum-chemical methods are able to calculate this cohesive energy taking into account all the interactions between occurring dimers in both first-and second-shells. These include both O(N(6))- and O(N(5))-scaling methods, Local Pair Natural Orbital-parameterized Coupled-Cluster Single and Double, and Spin-Component-Scaled-Møller-Plesset perturbation theory at second-order, respectively, as well as the most modern family of conceived density functionals: double-hybrid expressions in several variants (B2-PLYP, mPW2-PLYP, PWPB95) with customized dispersion corrections (-D3 and -NL). All-in-all, it is shown that these methods behave very accurately producing errors in the 1-2 kJ/mol range with respect to the experimental value taken into account the experimental uncertainty. These methods are thus confirmed as excellent tools for studying all kinds of interactions in chemical systems.