Observation of Stark many-body localization without disorder.

Thermalization is a ubiquitous process of statistical physics, in which a physical system reaches an equilibrium state that is defined by a few global properties such as temperature. Even in isolated quantum many-body systems, limited to reversible dynamics, thermalization typically prevails1. However, in these systems, there is another possibility: many-body localization (MBL) can result in preservation of a non-thermal state2,3. While disorder has long been considered an essential ingredient for this phenomenon, recent theoretical work has suggested that a quantum many-body system with a spatially increasing field-but no disorder-can also exhibit MBL4, resulting in 'Stark MBL'5. Here we realize Stark MBL in a trapped-ion quantum simulator and demonstrate its key properties: halting of thermalization and slow propagation of correlations. Tailoring the interactions between ionic spins in an effective field gradient, we directly observe their microscopic equilibration for a variety of initial states, and we apply single-site control to measure correlations between separate regions of the spin chain. Furthermore, by engineering a varying gradient, we create a disorder-free system with coexisting long-lived thermalized and non-thermal regions. The results demonstrate the unexpected generality of MBL, with implications about the fundamental requirements for thermalization and with potential uses in engineering long-lived non-equilibrium quantum matter.

Multicentric Analysis of the Species Distribution and Antifungal Susceptibility of Clinical Isolates from Aspergillus Section Circumdati.

The clinical involvement and antifungal susceptibility of Aspergillus section Circumdati are poorly known. We analyzed 52 isolates, including 48 clinical isolates, belonging to 9 species inside the section Circumdati. The whole section exhibited, by the EUCAST reference method, a poor susceptibility to amphotericin B, but species/series-specific patterns were observed for azole drugs. This underlines the interest in getting an accurate identification inside the section Circumdati to guide the choice of antifungal treatment in clinical practice.

Observation of a many-body dynamical phase transition with a 53-qubit quantum simulator.

A quantum simulator is a type of quantum computer that controls the interactions between quantum bits (or qubits) in a way that can be mapped to certain quantum many-body problems. As it becomes possible to exert more control over larger numbers of qubits, such simulators will be able to tackle a wider range of problems, such as materials design and molecular modelling, with the ultimate limit being a universal quantum computer that can solve general classes of hard problems. Here we use a quantum simulator composed of up to 53 qubits to study non-equilibrium dynamics in the transverse-field Ising model with long-range interactions. We observe a dynamical phase transition after a sudden change of the Hamiltonian, in a regime in which conventional statistical mechanics does not apply. The qubits are represented by the spins of trapped ions, which can be prepared in various initial pure states. We apply a global long-range Ising interaction with controllable strength and range, and measure each individual qubit with an efficiency of nearly 99 per cent. Such high efficiency means that arbitrary many-body correlations between qubits can be measured in a single shot, enabling the dynamical phase transition to be probed directly and revealing computationally intractable features that rely on the long-range interactions and high connectivity between qubits.

Observation of a discrete time crystal.

Spontaneous symmetry breaking is a fundamental concept in many areas of physics, including cosmology, particle physics and condensed matter. An example is the breaking of spatial translational symmetry, which underlies the formation of crystals and the phase transition from liquid to solid. Using the analogy of crystals in space, the breaking of translational symmetry in time and the emergence of a 'time crystal' was recently proposed, but was later shown to be forbidden in thermal equilibrium. However, non-equilibrium Floquet systems, which are subject to a periodic drive, can exhibit persistent time correlations at an emergent subharmonic frequency. This new phase of matter has been dubbed a 'discrete time crystal'. Here we present the experimental observation of a discrete time crystal, in an interacting spin chain of trapped atomic ions. We apply a periodic Hamiltonian to the system under many-body localization conditions, and observe a subharmonic temporal response that is robust to external perturbations. The observation of such a time crystal opens the door to the study of systems with long-range spatio-temporal correlations and novel phases of matter that emerge under intrinsically non-equilibrium conditions.

WASH infrastructure and practices in primary health care clinics in the rural Vhembe District municipality in South Africa.

BACKGROUND: South Africa has unique and diverse social and economic factors that have an impact on the provision of basic water, sanitation, hygiene and waste management infrastructure and practices at health care facilities in ensuring patient safety and prevent the spread of diseases. METHODS: The aim of this study was to evaluate water, sanitation and hygiene access and standards at 50 government owned public health care clinics in the rural region of the Vhembe district of South Africa during 2016/2017, using self-observation, an observation checklist, record reviews and interviews with clinic managers. Water quality from all available water sources on the clinic compound was analysed for Total coliform and E. coli counts using the Colilert Quanti-tray/2000 system. The prevalence of pathogenic diarrhea causing E. coli strains was established using multiplex-Polymerase Chain Reaction. RESULTS: The health care clinics in the Vhembe District generally complied with the basic WASH services guidelines according to the World Health Organisation. Although 80% of the clinics used borehole water which is classified as an improved water source, microbiological assessment showed that 38% inside taps and 64% outside taps from the clinic compounds had TC counts higher than guideline limits for safe drinking. Similarly, EC counts above the guideline limit for safe drinking water were detected in 17% inside taps and 32% outside taps from the clinic compounds. Pathogenic EAEC, EPEC, ETEC and EHEC strains were isolated in the collected water samples. Although improved sanitation infrastructures were present in most of the clinics, the sanitary conditions of these toilets were not up to standard. Waste systems were not adequately managed. A total of 90% of the clinics had hand washing basins, while only 61% of the clinics had soap present and only 64% of the clinics had adequate signs and posters reminding the staff, care givers and patients to wash their hands. CONCLUSIONS: Various WASH aspects within the primary health care system in South Africa needs to be improved and corrected. A more rigorous system that is inclusive of all role players in the WASH sectors, with regular monitoring and training sessions, should be used.

Unexpected mould diversity in clinical isolates from French Guiana and associated identification difficulties.

New mold species are increasingly reported in invasive fungal infections. However, these fungi are often misdiagnosed or undiagnosed due to the use of inappropriate laboratory diagnostic tools. Tropical countries, such as French Guiana, harbor a vast diversity of environmental fungi representing a potential source of emerging pathogens. To assess the impact of this diversity on the accuracy of mold-infection diagnoses, we identified mold clinical isolates in French Guiana during a five-month follow-up using both microscopy and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. In total, 38.8% of the 98 obtained molds isolates could not be identified and required a DNA-based identification. Fungal diversity was high, including 46 species, 26 genera, and 13 orders. Fungal ecology was unusual, as Aspergillus species accounted for only 27% of all isolates, and the Nigri section was the most abundant out of the six detected Aspergillus sections. Macromycetes (orders Agaricales, Polyporales, and Russulales) and endophytic fungi accounted for respectively 11% and 14% of all isolates. Thus, in tropical areas with high fungal diversity, such as French Guiana, routine mold identification tools are inadequate. Molecular identifications, as well as morphological descriptions, are necessary for the construction of region-specific mass spectrum databases. These advances will improve the diagnosis and clinical management of new fungal infections. LAY SUMMARY: In French Guiana, environmental fungal diversity may be a source of emerging pathogens. We evaluated microscopy and mass spectrometry to identify mold clinical isolates. With 39% of unidentified isolates, a region-specific mass spectrum database would improve the diagnosis of new fungal infections.

Bortezomib and Vorinostat Therapy as Maintenance Therapy after Autologous Transplant for Multiple Myeloma.

BACKGROUND: In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT. PATIENTS AND METHODS: We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles. RESULTS: The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12-9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression. CONCLUSIONS: BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.

[Assessment of Asbestos-related Occupational Diseases: Socio-medical and Legal Aspects]. / Sozialmedizinische und sozialjuristische Aspekte in der Zusammenhangsbegutachtung asbestbedingter Berufskrankheiten.

Occupational diseases are certain diseases designated as such by law. Whereas the medical conditions are described in guidelines, their recognition is based on judicial administrative procedures. Establishing causality is based on requirements of social law. The basic socio-legal concepts are mentioned and the principles of causality in asbestos-related occupational diseases are listed. Exemplary social court judgments are cited. Judgements may not infrequently differ from the medical point of view. The aim of this article is to describe the correct use of social medical understanding in order to carry out adequate assessment of occupational diseases, which implements the legal requirements.

Public Microbial Resource Centers: Key Hubs for Findable, Accessible, Interoperable, and Reusable (FAIR) Microorganisms and Genetic Materials.

In the context of open science, the availability of research materials is essential for knowledge accumulation and to maximize the impact of scientific research. In microbiology, microbial domain biological resource centers (mBRCs) have long-standing experience in preserving and distributing authenticated microbial strains and genetic materials (e.g., recombinant plasmids and DNA libraries) to support new discoveries and follow-on studies. These culture collections play a central role in the conservation of microbial biodiversity and have expertise in cultivation, characterization, and taxonomy of microorganisms. Information associated with preserved biological resources is recorded in databases and is accessible through online catalogues. Legal expertise developed by mBRCs guarantees end users the traceability and legality of the acquired material, notably with respect to the Nagoya Protocol. However, awareness of the advantages of depositing biological materials in professional repositories remains low, and the necessity of securing strains and genetic resources for future research must be emphasized. This review describes the unique position of mBRCs in microbiology and molecular biology through their history, evolving roles, expertise, services, challenges, and international collaborations. It also calls for an increased deposit of strains and genetic resources, a responsibility shared by scientists, funding agencies, and publishers. Journal policies requesting a deposit during submission of a manuscript represent one of the measures to make more biological materials available to the broader community, hence fully releasing their potential and improving openness and reproducibility in scientific research.

Factors influencing the clinical outcome of preimplantation genetic testing for polycystic kidney disease.

STUDY QUESTION: What are the factors influencing the success rate for couples undergoing preimplantation genetic testing (PGT) for polycystic kidney disease (PKD)? SUMMARY ANSWER: In our study cohort, the live birth delivery rate is significantly associated with female age while the male infertility accompanying autosomal dominant PKD (ADPKD) does not substantially affect the clinical outcome. WHAT IS KNOWN ALREADY: While women with ADPKD have no specific fertility problems, male ADPKD patients may present with reproductive system abnormalities and infertility. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study involves 91 PGT cycles for PKD for 43 couples (33 couples for PKD1, 2 couples for PKD2 and 8 couples for autosomal recessive PKD (ARPKD)) from January 2005 until December 2016 with follow-up of transfers until end of 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sixteen single-cell clinical tests for PKD based on multiplex PCR of short tandem repeat markers, with or without a specific mutation were developed and applied for diagnosis of 584 Day 3 cleavage stage embryos. In 18 couples, the male partner was affected with ADPKD (=Group A) and 12 of them had a documented infertility status. Group A underwent 52 cycles to oocyte retrieval. For 18 other couples, the female partner was affected with ADPKD (=Group B) and four male partners from this group had a documented history of infertility. This group underwent 31 cycles to OR. MAIN RESULTS AND THE ROLE OF CHANCE: Genetic analysis resulted in 545 embryos (93.3%) with a diagnosis, of which 215 (36.8%) were genetically transferable. Transfer of 74 embryos in 53 fresh cycles and of 34 cryopreserved embryos in 33 frozen-warmed embryo transfer cycles resulted in a live birth delivery rate of 38.4% per transfer with 31 singleton live births, two twin live births and one ongoing pregnancy. The observed cumulative delivery rate was 57.8% per couple after five treatment cycles. Thirty cryopreserved embryos still remain available for transfer. The clinical pregnancy rate per transfer (fresh + frozen; 45.9% in group A versus 60.0% in group B, P < 0.05) and the live birth delivery rate per transfer (fresh + frozen; 27.0% in group A versus 42.9% in group B, P < 0.05) was significantly lower for couples with the male partner affected with ADPKD compared with couples with the female partner affected with ADPKD. However, a multivariate logistic regression analysis showed that only female age was associated with live birth delivery rate (odds ratio = 0.87; 95% CI: 0.77-0.99; P = 0.032). LIMITATIONS, REASONS FOR CAUTION: This study is based on retrospective data from a single centre with Day 3 one-cell and two-cell biopsy. Further analysis of a larger cohort of PKD patients undergoing PGT is required to determine the impact of male infertility associated with ADPKD on the cumulative results. WIDER IMPLICATIONS OF THE FINDINGS: Knowledge about factors affecting the clinical outcome after PGT can be a valuable tool for physicians to counsel PKD patients about their reproductive options. Males affected with ADPKD who suffer from infertility should be advised to seek treatment in time to improve their chances of conceiving a child. STUDY FUNDING/COMPETING INTEREST(S): No funding was obtained. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Maternal investment in last-laid eggs does not compensate for hatching asynchrony in a seabird.

Maternal and environmental effects can have profound effects on offspring performance by generating variation in offspring phenotypes, independent of genetic effects. Within avian broods, differential maternal investment of resources across the laying sequence is thought to be an adaptive strategy to modulate competitive hierarchies induced by hatching asynchrony. In this study, we evaluated the relative importance of maternally derived within-clutch variation and the asymmetric post-hatching environment for growth and survival of common tern (Sterna hirundo) siblings. We experimentally manipulated hatching order, resulting in chicks from last-laid eggs hatching first and vice versa. Although both initial age and size asymmetries were larger within experimental than control broods, the early survival of last-hatched chicks was similar between groups. Initial positive effects of egg size disappeared as siblings approached fledging. Ultimately at fledging, both within-brood growth and cumulative survival patterns were similar between experimental and control broods, suggesting that the effects of systematic variation of egg constituents (e.g., maternally derived yolk hormones) and egg size are too subtle and largely overwhelmed by the effects of hatching asynchrony. Therefore, we conclude that variation in offspring phenotypes is pre-dominantly determined by the social environment experienced post-hatching. Maternal effects may further fine-tune phenotypic variation in response to varying environmental conditions, but this needs to be tested through empirical studies in which multiple maternal effects are measured simultaneously under different environmental conditions.

Drivers of changing urban flood risk: A framework for action.

This study focuses on drivers for changing urban flood risk. We suggest a framework for guiding climate change adaptation action concerning flood risk and manageability in cities. The identified key drivers of changing flood hazard and vulnerability are used to provide an overview of each driver's impact on flood risk and manageability at the city level. We find that identified drivers for urban flood risk can be grouped in three different priority areas with different time horizon. The first group has high impact but is manageable at city level. Typical drivers in this group are related to the physical environment such as decreasing permeability and unresponsive engineering. The second group of drivers is represented by public awareness and individual willingness to participate and urbanization and urban sprawl. These drivers may be important and are manageable for the cities and they involve both short-term and long-term measures. The third group of drivers is related to policy and long-term changes. This group is represented by economic growth and increasing values at risk, climate change, and increasing complexity of society. They have all high impact but low manageability. Managing these drivers needs to be done in a longer time perspective, e.g., by developing long-term policies and exchange of ideas.

Repository corticotrophin injection exerts direct acute effects on human B cell gene expression distinct from the actions of glucocorticoids.

Repository corticotrophin injection (RCI, H.P Acthar® gel) has been approved for use in the management of multiple autoimmune and inflammatory diseases for more than a half-century, but its mechanism of action is not well understood. We used RNA-Seq methods to define RCI-regulated mRNAs in cultured human B cells under conditions of activation by interleukin (IL)-4 and CD40 ligand. Following IL-4/CD40L activation and RCI treatment we found up-regulation of 115 unique mRNA transcripts and down-regulation of 80 unique mRNAs. The effect on these RNA levels was dose-dependent for RCI and was distinct from changes in mRNA expression induced by treatment with a potent synthetic glucocorticoid. RCI down-regulated mRNAs were observed to include a significant over-representation of genes critical for B cell proliferation under activating conditions. These data confirm that RCI exerts direct effects on human B cells to modulate mRNA expression in specific pathways of importance to B cell function and that, at the molecular level, the effects of RCI are distinct from those exerted by glucocorticoids.

A comparison between decomposition rates of buried and surface remains in a temperate region of South Africa.

Several studies have been conducted on decomposition patterns and rates of surface remains; however, much less are known about this process for buried remains. Understanding the process of decomposition in buried remains is extremely important and aids in criminal investigations, especially when attempting to estimate the post mortem interval (PMI). The aim of this study was to compare the rates of decomposition between buried and surface remains. For this purpose, 25 pigs (Sus scrofa; 45-80 kg) were buried and excavated at different post mortem intervals (7, 14, 33, 92, and 183 days). The observed total body scores were then compared to those of surface remains decomposing at the same location. Stages of decomposition were scored according to separate categories for different anatomical regions based on standardised methods. Variation in the degree of decomposition was considerable especially with the buried 7-day interval pigs that displayed different degrees of discolouration in the lower abdomen and trunk. At 14 and 33 days, buried pigs displayed features commonly associated with the early stages of decomposition, but with less variation. A state of advanced decomposition was reached where little change was observed in the next ±90-183 days after interment. Although the patterns of decomposition for buried and surface remains were very similar, the rates differed considerably. Based on the observations made in this study, guidelines for the estimation of PMI are proposed. This pertains to buried remains found at a depth of approximately 0.75 m in the Central Highveld of South Africa.

Validation of a New Web Application for Identification of Fungi by Use of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry.

Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry has emerged as a reliable technique to identify molds involved in human diseases, including dermatophytes, provided that exhaustive reference databases are available. This study assessed an online identification application based on original algorithms and an extensive in-house reference database comprising 11,851 spectra (938 fungal species and 246 fungal genera). Validation criteria were established using an initial panel of 422 molds, including dermatophytes, previously identified via DNA sequencing (126 species). The application was further assessed using a separate panel of 501 cultured clinical isolates (88 mold taxa including dermatophytes) derived from five hospital laboratories. A total of 438 (87.35%) isolates were correctly identified at the species level, while 26 (5.22%) were assigned to the correct genus but the wrong species and 37 (7.43%) were not identified, since the defined threshold of 20 was not reached. The use of the Bruker Daltonics database included in the MALDI Biotyper software resulted in a much higher rate of unidentified isolates (39.76 and 74.30% using the score thresholds 1.7 and 2.0, respectively). Moreover, the identification delay of the online application remained compatible with real-time online queries (0.15 s per spectrum), and the application was faster than identifications using the MALDI Biotyper software. This is the first study to assess an online identification system based on MALDI-TOF spectrum analysis. We have successfully applied this approach to identify molds, including dermatophytes, for which diversity is insufficiently represented in commercial databases. This free-access application is available to medical mycologists to improve fungal identification.

Spectrum of mutations in cystinuria patients presenting with prenatal hyperechoic colon.

Cystinuria is a heterogeneous, rare but important cause of inherited kidney stone disease due to mutations in 2 genes: SLC3A1 and SLC7A9. Antenatal hyperechoic colon (HEC) has been reported in some patients as a non-pathological consequence of the intestinal transport defect. We report 83 patients affected by cystinuria: 44 presented prenatally with a HEC (HEC group) and 39 with a classical postnatal form (CC group). SLC3A1 and SLC7A9 were sequenced. All patients were fully genotyped, and the relationship between the genotype and clinical features was analyzed. We identified mutations in SLC3A1 in 80% of the HEC group and in only 49% of the CC group. The SLC3A1 p.Thr216Met mutation was found in 21% of the alleles in the HEC group but was never found in the CC group. Most of the mutations found in the HEC group were considered severe mutations in contrast with the CC group. Twenty-five novel mutations were reported. This study shows a relationship between genotype and the clinical form of cystinuria, suggesting that only the patients with the most severe mutations presented with an HEC. These results emphasized the need for prenatal cystinuria screening using classical third-trimester ultrasound scan and the early management of suspected newborns.

Assessment of Atopobium vaginae and Gardnerella vaginalis concentrations in a cohort of pregnant South African women.

OBJECTIVES: The purpose of this cross-sectional study was to assess Atopobium vaginae and Gardnerella vaginalis concentrations in pregnant women of different age groups, gestational age groups, vaginal flora categories and HIV status, and also to determine which DNA concentrations best discriminated between bacterial vaginosis (BV)-positive and non-BV categories. METHODS: Self-collected vaginal swabs were obtained from 220 pregnant women attending an antenatal clinic in Pretoria, Gauteng, South Africa, from July 2012 to December 2012. BV was detected with the Nugent scoring system, and A. vaginae and G. vaginalis DNA was quantified with a multiplex quantitative real-time PCR assay. RESULTS: Median concentrations of A. vaginae and G. vaginalis were not significantly different among various age groups (A. vaginae p=0.98 and G. vaginalis p=0.18) or different trimesters (A. vaginae p=0.31 and G. vaginalis p=0.19), but differed significantly among the vaginal flora categories (A. vaginae p<0.001 and G. vaginalis p<0.001) and HIV status (A. vaginae p<0.001 and G. vaginalis p=0.004). The presence of A. vaginae (OR=5.8; 95% CI 1.34 to 25.21 and p value=0.02) but not that of G. vaginalis (OR=1.90; 95% CI 0.81 to 4.43 and p value=0.14) was associated with HIV infection. An A. vaginae DNA concentration of ≥107 copies/mL together with a positive G. vaginalis result (≥100 copies/mL) best discriminated between BV-positive (39/220) and non-BV categories (181/220) with a sensitivity of 85% (95% CI 0.70 to 0.94) and a specificity of 82% (95% CI 0.76 to 0.88). CONCLUSIONS: A. vaginae and G. vaginalis were present in high numbers and concentrations in this pregnant cohort. Threshold concentrations should be established for specific populations to ensure sensitive molecular assays for BV detection.

Non-thermalization in trapped atomic ion spin chains.

Linear arrays of trapped and laser-cooled atomic ions are a versatile platform for studying strongly interacting many-body quantum systems. Effective spins are encoded in long-lived electronic levels of each ion and made to interact through laser-mediated optical dipole forces. The advantages of experiments with cold trapped ions, including high spatio-temporal resolution, decoupling from the external environment and control over the system Hamiltonian, are used to measure quantum effects not always accessible in natural condensed matter samples. In this review, we highlight recent work using trapped ions to explore a variety of non-ergodic phenomena in long-range interacting spin models, effects that are heralded by the memory of out-of-equilibrium initial conditions. We observe long-lived memory in static magnetizations for quenched many-body localization and prethermalization, while memory is preserved in the periodic oscillations of a driven discrete time crystal state.This article is part of the themed issue 'Breakdown of ergodicity in quantum systems: from solids to synthetic matter'.

Phenotype-associated inbreeding biases estimates of inbreeding depression in a wild bird population.

Inbreeding depression is usually quantified by regressing individual phenotypic values on inbreeding coefficients, implicitly assuming there is no correlation between an individual's phenotype and the kinship coefficient to its mate. If such an association between parental phenotype and parental kinship exists, and if the trait of interest is heritable, estimates of inbreeding depression can be biased. Here we first derive the expected bias as a function of the covariance between mean parental breeding value and parental kinship. Subsequently, we use simulated data to confirm the existence of this bias, and show that it can be accounted for in a quantitative genetic animal model. Finally, we use long-term individual-based data for white-throated dippers (Cinclus cinclus), a bird species in which inbreeding is relatively common, to obtain an empirical estimate of this bias. We show that during part of the study period, parents of inbred birds had shorter wings than those of outbred birds, and as wing length is heritable, inbred individuals were smaller, independent of any inbreeding effects. This resulted in the overestimation of inbreeding effects. Similarly, during a period when parents of inbred birds had longer wings, we found that inbreeding effects were underestimated. We discuss how such associations may have arisen in this system, and why they are likely to occur in others, too. Overall, we demonstrate how less biased estimates of inbreeding depression can be obtained within a quantitative genetic framework, and suggest that inbreeding and additive genetic effects should be accounted for simultaneously whenever possible.