Immunoglobulin G4 (IgG4)-related disease is a systemic disease characterized by sclerosing lesions and an increased serum IgG4 level. This condition can involve any organ, but IgG4-related spinal pachymeningitis is relatively rare. In the current study, we report a case of spinal cord compression caused by IgG4-related spinal pachymeningitis. A 39-year-old man presented to us with a 15-day history of back pain and a 3-day history of dysuresia, exacerbated by weakness in the lower extremities for 2 days. Cervical magnetic resonance imaging (MRI) showed strip-shaped abnormal signals along the anterior and posterior borders of the spinal cord at the C5–T4 levels. The IgG level in cerebrospinal fluid was 718.0 mg/L. Thoracic MRI revealed strip-shaped abnormal signals with remarkable enhancement along the anterior and posterior borders of the dural sac at the T1–T6 levels. Histopathological examination confirmed IgG4-related spinal pachymeningitis. The symptoms worsened rapidly, and surgical resection of the space-occupying lesion in the vertebral canal was performed for spinal decompression. Corticosteroid therapy was administered, and the patient's motor functions were mildly improved. IgG4-related disease can manifest as spinal pachymeningitis and cause spinal cord compression. Clinicians should be aware of this rare condition, and early diagnosis, timely surgical decompression, and appropriate corticosteroid therapy should be highlighted. Immunoglobulin G4 (IgG4)-related disease is a systemic disease characterized by sclerosing lesions and an elevated serum IgG4 level. This disease can involve virtually any organ, and pancreas, salivary glands, and lacrimal glands are most commonly affected. In addition, IgG4-related central nervous system (CNS) involvement is a rare and distinct entity of IgG4-related disease , with hyA 39-year-old previously healthy man presented to us with a 15-day history of back pain and a 3-day history of dysuresia, exacerbated by weakness in the lower extremities for 2 days. One day prior to admission, he was unable to walk or urinate. He denied any history of hypertension, diabetes, heart diseases, infectious diseases, or trauma as well as any history of direct contact with cattle or sheep or tuberculosis. On admission, physical examination showed a loss of sensation below the T12 dermatome, spinal tenderness at the T2 level, and muscle strength of grade 3/5 in the bilateral lower extremities. Additionally, there was radicular pain during cervical anteflexion. The muscular tone was normal in all extremities. The proprioceptive sensation in the lower extremities was also decreased, and the abdominal and cremasteric reflexes disappeared. Ankle clonus, Hoffmann sign, Babinski sign, and Chaddock sign were positive for bilateral extremities. On the second day after admission, the lower extremity weakness was exacerbated. Neurological reexamination showed a loss of sensation below the T8 dermatome and a muscle strength of grade 2/5 in the bilateral lower extremities; nevertheless, the bilateral pathological reflexes  were all negative.2O. The protein level was elevated (2.7 g/L), and Pandy's test showed strong positivity. Cell counting showed elevated leukocytes (31 × 106/L) and erythrocytes (400 × 106/L) with a lymphocyte ratio of 98% and a monocyte ratio of 7%. The IgG level in the CSF was 718.0 mg/L. The CSF smear and IgG antibody for tuberculosis were negative, and quantitative examination and agglutination test for brucellosis were negative as well.Cervical magnetic resonance imaging (MRI) showed strip-shaped abnormal signals along the anterior and posterior borders of the spinal cord at the C5–T4 levels , upper. After admission, methylprednisolone  was administered intravenously. Considering that the subdural extramedullary lesion might be caused by a hematoma or tuberculosis, methylprednisolone was used for 2 days and then replaced by an antituberculosis therapy. Five days later, the symptoms became aggravated. Cervicothoracic MRI revealed strip-shaped abnormal signals along the anterior and posterior borders of the dural sac at the T1–T6 levels , lower. Intraoperatively, the lesion showed a rubber-like appearance with a hard nature, and it was distributed extensively on the dura mater. The dura mater had no pulsation with a high tension. After the dura mater was incised, a subdural lesion was noted with a rubber-like appearance as well, and the spinal cord was compressed. The subdural and epidural lesions were resected for decompression. The post-operative course was uneventful. Physical examination showed a loss of sensation below the T4 dermatome, and muscle strength of grade 0/5 in the bilateral lower extremities. The bilateral pathological reflexes (Babinski sign and Chaddock sign) were all positive.Histopathological examination showed diffuse infiltration of inflammatory cells within the fibrofatty tissue, and numerous plasma cell infiltrates could be noted . ImmunohFurther laboratory examination revealed an IgG4 level of 1.050 g/L, an erythrocyte sedimentation rate of 120 mm/1 h, and a C-reactive protein level of 115 mg/L. Based on the clinical and histopathological profiles, a diagnosis of spinal cord compression caused by IgG4-related spinal pachymeningitis was made. Corticosteroid therapy was scheduled . Two dayautoimmune pancreatitis,” and then in 2001, autoimmune pancreatitis was found to be related to IgG4-positive plasma cells , with a significant male predominance , 15. CliAlthough the majority of IgG4-related diseases are characterized by elevated serum levels of IgG and IgG4, according to the literature, IgG and IgG4 can also remain within the normal ranges in 30 and 8% of all patients, respectively , 19. ThuThe identification of IgG4-related diseases should depend on comprehensive evaluation including clinical manifestations, laboratory examinations, radiological features, and histopathological findings, and the gold standard is histopathology and immunohistochemistry. We summarized a diagnosis flow as shown in Cervicothoracic spinal cord compression caused by IgG4-related disease is extremely rare . As the IgG4-related pachymeningitis is rare and was first reported in 2009 . As one All the symptomatic and active IgG4-related diseases need timely treatment. For the primary treatment, glucocorticoids are the first choice for inducing remission. Moreover, for patients who respond poorly to glucocorticoids and those who experience recurrence, addition of immunosuppressors can be attempted. Currently, there is no specific treatment for IgG4-related pachymeningitis. Short-term efficacy of surgery in single-organ IgG4-related pachymeningitis is good and, in some cases, may be sufficient to achieve remission . When muIn conclusion, the clinical presentations and radiological characteristics of IgG4-related CNS diseases are non-specific. The definitive diagnosis should depend on histopathology and immunohistochemistry. Spinal cord compression caused by IgG4-related disease is extremely rare and may progress rapidly, leading to severe neurological deficits. Timely surgical decompression with subsequent systemic corticosteroid treatment is needed.The datasets generated for this study can be found within the article.This study was approved by the ethics committee of the First Hospital of Jilin University, Changchun, China. Written informed consent was obtained from the patient for the publication of this case report.RZ, JG, and TZ contributed to the conception and design of the study. BZ and LC organized the database. CheW and ChaW performed the statistical analysis and wrote the first draft of the manuscript. JG, JC, TZ, and RZ wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Given the central role of radiology in patient care, it is important that radiological research is grounded in reproducible science. It is unclear whether there is a lack of reproducibility or transparency in radiologic research.To analyze published radiology literature for the presence or lack of key indicators of reproducibility.This cross-sectional retrospective study was performed by conducting a search of the National Library of Medicine (NLM) for publications contained within journals in the field of radiology. Our inclusion criteria were being MEDLINE indexed, written in English, and published from January 1, 2014, to December 31, 2018. We randomly sampled 300 publications for this study. A pilot-tested Google form was used to record information from the publications regarding indicators of reproducibility. Following peer-review, we extracted data from an additional 200 publications in an attempt to reproduce our initial results. The additional 200 publications were selected from the list of initially randomized publications.Our initial search returned 295,543 records, from which 300 were randomly selected for analysis. Of these 300 records, 294 met inclusion criteria and 6 did not. Among the empirical publications, 5.6%  contained a data availability statement, 0.51% (1/195) provided clear documented raw data, 12.0%  provided a materials availability statement, 0% provided analysis scripts, 4.1%  provided a pre-registration statement, 2.1%  provided a protocol statement, and 3.6%  were pre-registered. The validation study of the 5 key indicators of reproducibility—availability of data, materials, protocols, analysis scripts, and pre-registration—resulted in 2 indicators  being reproduced, as they fell within the 95% confidence intervals for the proportions from the original sample. However, materials’ availability and pre-registration proportions from the validation sample were lower than what was found in the original sample.Our findings demonstrate key indicators of reproducibility are missing in the field of radiology. Thus, the ability to reproduce studies contained in radiology publications may be problematic and may have potential clinical implications. Key indicators of reproducibility and transparency are frequently missing in the radiology literature.The ability to reproduce the results of radiologic studies may be difficult.The field of radiology plays a significant role in the diagnosis, monitoring, and treatment of numerous disease processes. The importance of radiology to the field of medicine is evident by the large amount of annual expenditures on imaging, estimated to be 10% of total healthcare costs in the USA . With thReproducibility—defined as the ability to conduct an independent replication study and reach the same or similar conclusions as the study in question , 4—gaineGiven the central role of radiology to patient care, reproducible radiology research is necessary. In this study, we investigate radiology publications for key factors of reproducibility and transparency. Findings may be used to evaluate the current climate of reproducible research practices in the field and contribute baseline data for future comparison studies.https://osf.io/n4yh5/). Amendments to our study, based upon peer review feedback following initial submission, are described in the protocol.Our investigation was designed as a cross-sectional meta-research study to evaluate specific indicators of reproducibility and transparency in radiology. The study methodology is a replication of work done by Hardwick et al.  with minhttps://osf.io/n4yh5/). With the goal of creating a diverse spectrum of publications for our study, restrictions were not placed on specific study types.One investigator (D.T.) searched PubMed with the NLM subject term tag “Radiology[ST]” on June 5, 2019. D.T. extracted the electronic ISSN number (or linking ISSN if the electronic version was unavailable) for included journals. PubMed was searched using the list of ISSN (PubMed contains the MEDLINE collection) on June 5, 2019, to identify publications. A random sample of 300 was selected to have data extracted with additional publications available as needed (https://osf.io/tf7nw/).Three investigators  underwent rigorous in-person training led by D.T. on data extraction and study methodology to ensure reliability between investigators. Training included a review of the following: objectives of the study, design of the study, protocol, Google form used for data extraction, and the process of extracting data. The process for extracting data was demonstrated via the use of 2 example publications. All investigators who underwent training independently conducted a blinded and duplicate extraction of data from 2 example publications. Once the mock data extraction was completed, the investigators  convened and resolved any discrepancies present. The entire training session was recorded from the presenters’ point of view and was posted online for investigators to reference  performed data extraction on 300 publications with the other two investigators (N.V. and J.N.) extracting from 150 each. We divided publications into two categories: (1) publications with empirical data  and (2) publications without empirical data. For the sake of this study, imaging protocols with no patients or intervention were considered non-empirical. Different study designs resulted in a variation of data collected from individual publications. We analyzed non-empirical studies for the following characteristics: funding source(s), conflict of interest declarations, open access, and journal impact factor . Case reports and case series are not typically expected to be reproducible with a pre-specified protocol . As a rek et al.  used. Ouhttps://openaccessbutton.org/) was used to perform a search using publication title, DOI, and/or PubMed ID. If search parameters resulted in an inaccessible article, Google Scholar and PubMed were searched using these parameters. If an investigator was still unable to locate a full-text publication, it was deemed inaccessible.We systematically evaluated the accessibility of a full-text version of each publication. The Open-Access Button  the number of times a publication was used as part of a subsequent replication study and (2) the number of times a publication was cited in a systematic review/meta-analysis. Titles, abstracts, and full-text manuscripts available on the Web of Science were used to analyze if a study was cited in a systematic review/meta-analysis or a replication study.Following peer-review, we extracted data from an additional 200 publications in an attempt to validate our results from the original 300. The additional 200 studies were selected from the list of initially randomized publications. The same authors  extracted data from the studies in a blind and duplicate manner identical to the original sample.Dunnigan 2008.Statistics from each category of our analysis were calculated using Microsoft Excel. Excel functions were used to provide quantitative analysis with results characterized by frequencies, percentages, and 95% confidence intervals using the Wilson Score for binomial proportions The NLM catalog search identified 144 radiology journals, but only 64 met the inclusion criteria. Our PubMed search of journals identified 295,543 radiology publications with 53,328 being published within the time-frame. We randomly sampled 300, but only 294 publications were accessible. Of the eligible publications, 215 contained empirical data and 79 did not  = 2.83, p = .06]. Nearly half  of the eligible publications required paywall access. A correlation analysis found that publications that were not freely available through open access contained less indicators of reproducibility (r = − .51). More than half of the publications failed to provide a funding statement . Public funding accounted for 16% (47/294) of analyzed publications. The authors reported having no conflicts of interest (COI) in the majority of publications . No COI statement was provided 34.0% (100/294) of the time.From our sample of 294 radiology publications, the publishing journals had a median 5-year impact factor of 2.824 (interquartile range 1.765–3.718). Study designs of sampled publications are made available in Table Table Publication characteristics of the validation sample were very similar across all characteristics listed in Table Our cross-sectional investigation found that key transparency and reproducibility-related factors were rare or entirely absent among our sample of publications in the field of radiology. No analyzed publications reported an analysis script, a minority provided access to materials, few were pre-registered, and only one provided raw data. While concerning, our findings are similar to those found in the social science and biomedical literature , 12. HerOne factor that is important for reproducible research is the availability of all raw data. In radiology, clinical data and research data are often stored and processed in online repositories. Picture archives and communication systems, such as Digital Imaging and Communications in Medicine (DICOM), allow researchers to observe data code for details for image acquisition, patient positioning, image depth, and bit depth of an image . For exaGitHub.com to provide the exact coding used to analyze study data. Authors can go one step further and provide their data analysis in a “container” such as docker or singularity, which replicate the study calculations in real time while being applicable to other data sets [A second factor lacking in radiology literature was having detailed analysis scripts publically available. In radiology research, many analytic decisions exist ranging from data management, artificial intelligence algorithms, biomarker identification with validation, and sharing necessary items  –25. A syata sets . Investiata sets . Triphanata sets , 31. TheOur sample indicates there is room for improvement for the reporting of reproducibility-related factors in radiologic research. Ninety percent of scientists agree that science is currently experiencing a “reproducibility crisis” . When asTo create transparent and reproducible research, improved reporting is needed. For example, a study found irreproducible publications frequently contain inadequate documentation, reporting of methods, inaccessible protocols, materials, raw datasets, and analysis scripts , 12. We The current reproducibility crisis in part is tied to poor statistics. In psychology, a large-scale reproducibility study found that only 39 of 100 original psychology studies could be successfully replicated . In respQuality research practices are constantly evolving, requiring authors to continually stay up to date, or risk being uninformed. Research mentors should oversee the continual education for graduate students, post-docs, fellows, researchers, and health care providers on areas such as experimental design, statistical techniques, and study methodology. We encourage multi-center collaboration and team science, where cohorts of scientists implement the same research protocols to obtain highly precise and reproducible findings –47.Gundersen et al. 2017. Clinical radiology has shown similar increased usage of AI with the advent of algorithms to identify common pathology on chest films with an end goal of being applied to CTs or MRIs. In order for these imaging modalities to become a reality for clinicians, AI must be tested to produce reproducible findings and accurate diagnosis. Reproducibility and generalizability of AI results can be achieved for researchers and clinicians through the use of agreed-upon benchmarking data sets, performance metrics, standard imaging protocols, and reporting formats Hosny et al. 2018.Artificial intelligence (AI) has become an emerging tool within the field of radiology for physicians and researchers alike. The reproducibility of AI results in research projects is important as more data are being recorded and computed by programs without human intervention Cochrane Handbook [Regarding strengths, we randomly sampled a large selection of radiology journals. Our double data extraction methodology was performed in a similar fashion to systematic reviews by following the Handbook . CompletWith the potential lack of transparency and reproducibility practices in radiology, opportunities exist to improve radiology research. Our results indicate important factors for reproducibility and transparency are frequently missing in the field of radiology, leaving room for improvement. Methods to improve reproducibility and transparency are practical and applicable to many research designs.


Quartz sandstone (QS) is a mine waste; therefore, its use in construction allows for both reducing the cost of the concrete and contributing to the utilization of waste. The scientific originality of this study is the identification of models of the effect of QS aggregate on the physicomechanical, durability characteristics, and eco-safety of greener high-strength concrete. The study used an energy-efficient method of non-thermal effects of electromagnetic pulses on the destruction mechanisms of quartz-containing raw materials. The characteristics of quartzite sandstone aggregates, including the natural activity of radionuclides, were comprehensively studied. The features of concrete hardening, including the formation of an interfacial transition zone between the aggregate and the cement matrix, were studied, taking into account the chemical and morphological features of quartzite sandstone. In addition, the microstructural and morphological properties of concrete were determined after a 28 day curing. In this study, the behaviors of the concrete with QS aggregate were investigated, bearing in mind the provisions of geomimetics science on the affinity of structures. The results obtained showed that the QS aggregate had the activity of natural radionuclides 3–4 times lower compared to traditional aggregates. Efficient greener concrete with a 46.3 MPa compressive strength, water permeability grade W14, and freeze–thaw resistance of 300 cycles were also obtained, demonstrating that the performance of this greener concrete was comparable to that of traditional concrete with more expensive granite or gabbro diabase aggregates. The current stage of the development of civilization is characterized by a deteriorating environmental situation, a lack of energy resources as well as natural and technological disasters ,2,3. A pMany authors have worked on research to develop innovative sustainable concrete and/or mortar utilizing some aggregates. Longo et al.  obtainedOf great importance is the cost of aggregates while taking care of the environment. An effective step along this path is the use of simultaneously produced rocks.Granite, gravel, and limestone are the most popular and widespread sources of crushed stone, which are expensive, and their deposits are not available in all countries . The seaThe goal of the paper was to study the possibility of using quartz sandstone, which is simultaneously mined rock, as aggregate for greener high-strength concrete. To achieve this goal, the following tasks were solved, the determination of the activity of natural radionuclides of the QS aggregate, the development of greener high-strength concrete using quartz sandstone (screening as fine aggregate and crushed stone as coarse aggregate), and the study of the physicomechanical properties and durability characteristics of developed concrete.As a coarse aggregate, quartz sandstones of the Lebedinsky deposit (Russia) were used a, which Thus, according to the main indicators, crushed stone from quartz sandstone meets regulatory requirements. The value of intergranular voidness of crushed stone from QS indicates the potential of improving its particle size distribution. Low water absorption of crushed stone from quartz sandstone reduces the water demand of concrete mixes.Samples of crushed stone from quartz sandstone consisted of 95% quartz of the green shale degree of metamorphism. Its quality assessment is based on the internal energy potential, which is determined by the imperfection of the crystal lattice of minerals, inclusions of a mineral-forming medium, gas–air inclusions, surface morphology, degree of crystallinity of minerals, dimension, etc. Thus, based on the study of the mineralogical composition, chemical composition, and structure of the QS mining waste of the Lebedinsky deposit, it can be concluded that all samples met the requirements for raw materials for the production of crushed stone. All experiments were carried out using Portland cement CEM I 42.5N , satisfying the requirements of EN 197-1 ,28,29. T3  consumption of crushed stone of all types. The slump of concrete mixes was 16 cm with a mass ratio of sand to the total aggregates equal to 0.4. To obtain the specified strength characteristics (concrete of classes C 25 and C 30), as well as to identify the potential capabilities of coarse aggregate from quartz sandstone, the cement consumption when selecting the composition of concrete varied from 350 to 400 kg/m3 .To evaluate the granulometric composition of the materials, a MicroSizer 201 laser particle analyzer  was used, which made it possible to determine particles with a size from 0.2 to 600 μm. The specific surface area of raw materials and binders was determined by gas permeability using a PSH-11 device. An ARL X’TRA device  was used for X-ray diffraction (XRD) analysis. The microstructure was studied using a high-resolution scanning electron microscope TESCAN MIRA 3 LMU . The X-ray fluorescence (XRF) pattern was also investigated by scanning electron microscope.The specific effective activity of natural radionuclides of crushed stone was researched using a Gamma Plus universal spectrometric complex  according to Russian State Standard GOST 30108-94 .3 according to EN 12390-3:2009 [Determination of the compressive strength was carried out on specimen cubes with sizes 150 × 150 × 150 mm0-3:2009 . The spe3 in accordance with EN 12390-9:2006 [The freeze–thaw resistance of the specimens was researched by the method of alternate freezing and thawing on cubes of 70 × 70 × 70 mm0-9:2006 . The spe3 in size. For this, a setup having 6 sockets was used. Water was supplied to the lower end part. Visual observation of the resistance to water with increasing pressure was conducted. Furthermore, a flow chart of the studies is provided in The water resistance of concrete was estimated by the “wet spot” on the specimens—cylinders 100 × 100 × 150 mmTo maximize the disclosure of the stored energy of raw materials and their directed use while reducing the energy intensity of the technological process for producing building composites, the methods of chemical, thermal, and mechanical activation were used. The article used an energy-efficient, environmentally friendly method of non-thermal effects of electromagnetic pulses on the destruction mechanisms of quartz-containing raw materials. When current flows with extremely high power but moderately low energy through the matrix of mineral components, electrical breakdown channels as well as induced fracture zones are formed. This leads to the softening of mineral complexes with the formation of highly dispersed particles of increased activity and solves the problem of the destruction of raw materials. As a result, the number and nomenclature of hydration products increases and the density of the concrete increases; this leads to an increase in the mechanical properties of concrete.According to the provisions of geomimetics science on the affinity of structures proposed by Lesovik , for deseffA was determined. In order to obtain the value of effA, the specific activity of radium 226Ra—RaA, thorium 232Th—ThA, and potassium 40K—KA was measured and summarized according to the formula: effA = RaA + 1.31ThA + 0.085KA —is ensured.Granite consists of 30–35% quartz, approximately 60% feldspars, and the rest is mica. The cleavage of feldspars is perfect, but that of mica is very perfect. The adhesion to cement paste for feldspars and mica is very low, so granites cannot be used to produce high-strength concrete ,18. GabbIn the granite structure, quartz does not have as many crystal lattice defects as in quartz sandstone, which explains its lower reactivity. The ITZ is less dense; microcracks are present in it . This is3, the water resistance of concrete corresponded to the W6 grade, and with an increase in cement consumption to 400 kg/m3, it increased to W12–W14. The freeze–thaw resistance of the concrete complied with grades F200 and F300.For structural materials operating in environmental conditions, weather resistance is of great importance, which affects the durability characteristics. Thus, concrete with a crushed stone from quartz sandstones exceeds a similar type of concrete from granite or gabbro diabase crushed stone in strength. The value of compressive strength corresponded to classes C25 and C30. An increase in compressive strength by 14% in concrete with quartz sandstone indicates the possibility of reducing the consumption of cement in such concrete.3, the water resistance of the concrete corresponded to the W6 grade, and with an increase in cement consumption to 400 kg/m3, it increased to W12–W14. The freeze–thaw resistance of the concrete complied with grades F200 and F300. Thus, concrete with crushed stone from quartz sandstones exceeded similar types of concrete with granite or gabbro diabase crushed stone in strength. The value of compressive strength corresponded to classes C25 and C30. An increase in compressive strength by 14% in concrete with quartz sandstone indicates the possibility of reducing the consumption of cement in such concrete.It was established that the use of crushed stone from quartz sandstone provided greater freeze–thaw resistance and water resistance compared to the gabbro diabase or granite specimens. The test results indicated high durability of the obtained concrete. When cement consumption was 350 kg/mThe economic efficiency of the results of the work was to reduce the cost of aggregates through the use of mine waste. In addition to the fact that this waste had no value, it can also generate income for the one who is utilizing it. The environmental objective achieved along with this makes it possible to consider the developed material with the use of aggregates from mine waste as cost-effective and environmentally effective.−Quartz sandstone, which is a mine waste, can be used as aggregate for a high-strength, greenest concrete;−The activity of natural radionuclides of the tested aggregate from quartz sandstone is 3–4 times lower than that of traditional types of crushed stone: granite and gabbro diabase;−The use of a crushed stone from QS provides concrete with strength corresponding to grades C25 and C30. Mechanical properties of cement composite with coarse aggregate from quartz sandstone are 12–15% higher compared to concrete from traditional ones;−3 corresponded to grades F200 and W8, respectively, and with a cement consumption of 400 kg/m3 corresponded to grades F300 and W14, respectively.The freeze–thaw and water resistance of concrete on crushed stone from QS provides a sufficient level of durability. The indicators of freeze–thaw and water resistance of concrete with a cement consumption of 300 kg/mQuartz sandstone is a mine waste; therefore, its use in construction allows both for reducing the cost of the concrete and contributing to the utilization of waste. The novelty of this study is the identification of models of the effect of QS aggregate on the physicomechanical, durability characteristics, and eco-safety of concrete. In the investigation campaign, the properties of greener high-strength concrete made with QS aggregate was investigated, bearing in mind the provisions of geomimetics science on the affinity of microstructures. Results were obtained on the properties of aggregate made of quartz sandstones activated by non-thermal effects of electromagnetic pulses as well as the heavyweight concrete based on it. On the basis of the results obtained, the following conclusions are listed:Furthermore, the perspectives for further scientific research can be directed to the possibility of obtaining aggregates from incidentally mined rocks for the creation of various building products. This will contribute to the expansion of the range of local raw materials used to obtain concrete components and the expansion of the field of research in the direction of studying the features of the processes of structure formation of composites using various fine and coarse aggregates.


A two-level logistic regression model determined the association between diagnostic uncertainty factors and physician antibiotic prescribing. Physicians perceived a higher frequency of diagnostic uncertainty resulting in higher antibiotic use for URTIs and less antibiotic use for pneumonia. Higher antibiotic use for acute tonsillitis was related to a low tolerance of uncertainty of physicians and patients. This study suggests that reducing diagnostic uncertainty and improving physician and patient uncertainty management could reduce antibiotic use.This study aimed to determine the association between factors relevant to diagnostic uncertainty and physicians’ antibiotic-prescribing behaviour in primary care. A questionnaire survey was conducted on 327 physicians that measured their diagnostic ability, perceived frequency of diagnostic uncertainty, tolerance, and perceived patient tolerance of uncertainty. Physician antibiotic-prescribing behaviours were assessed based on their prescriptions ( There is little doubt that high levels of antibiotic consumption contribute to the development of antibiotic resistance2. Over 80% of antibiotics are prescribed in primary care facilities2. Irrational antibiotic prescribing in these facilities is common all over the world, including in countries where the antibiotic prescription rate is relatively low. General practitioners in the Netherlands, for example, are relatively less likely to prescribe antibiotics than their counterparts in other countries. However, antibiotic prescribing for patients without an indicative condition remains as high as 59%3.Antibiotic resistance is increasingly recognized as a major threat to global health and economic development4. Unfortunately, a diagnosis cannot always be established in primary care due to restrictions in resources and diagnostic capacities5. The complexity of pathogens adds further challenges to prescribing decisions6. Acute tonsillitis, for example, can be caused by viruses or bacteria7. A lack of certainty in the diagnosis of illness conditions and pathogens has been blamed for fuelling the over-prescriptions of antibiotics11.Theoretically, a clear diagnosis is fundamental to guide rational antibiotic prescriptions. The conditions that are most likely to be caused by bacteria are indicative of antibiotic use11, regardless of whether this situation is common in medical practices and is unlikely to disappear in the foreseeable future. Both physicians and patients have to learn to live with uncertainty.However, our understanding of how diagnostic uncertainty influences physician use of antibiotics is limited9, physician’s diagnostic ability12, and physician and patient tolerance of diagnostic uncertainty14. Existing studies have shown that decrease of physicians’ diagnostic uncertainty has reduced the rates of antibiotic prescription for patients in primary care9. Accordingly, it can be expected that where less diagnostic uncertainty takes place, fewer antibiotics are prescribed. It was also shown that nearly half of the irrational use of antibiotics in primary care was due to a deficit in physician’s diagnostic ability12. Furthermore, physician and patient tolerance of uncertainty has also been shown to have an impact on clinical decisions14. These factors may be important when deciding between “tolerance-sensitive” choices14: decisions where clinical evidence does not clearly support antibiotic prescription or not and may depend on physician and patient tolerance of uncertainty. However, the effect of these factors on physicians’ antibiotic-prescribing beahaviours has rarely been considered in existing studies.Based on existing research, several factors of physicians relevant to diagnostic uncertainty seemed to play a role contributing to the overuse of antibiotics, including the frequency of diagnostic uncertaintyThus, this study aimed to determine the association between several factors relevant to the diagnostic uncertainty of physicians and their antibiotic-prescribing behaviours in primary care.The majority of the extracted prescriptions were issued for patients younger than 18 years (35.03%) or between the age of 40 and 64 years (32.96%). Slightly more than half (51.86%) of the patients were male. Approximately 62.68% of the prescriptions contained antibiotics  and aged between 40 and 59 years (63.3%). Nearly two-thirds (64.22%) were general practitioners. Most respondents (74.62%) had over ten years of clinical experience. The vast majority (81.65%) reported attendance of antibiotic-prescribing training.Approximately 30% of the physician respondents reported a frequency of higher than 40% diagnostic uncertainty in medical practices. The mean score of diagnostic ability rated by the respondents reached 3.36 SD = 1.14), approximately 67% of the maximum score of five. Less than half (48.93%) obtained a score higher than three. Physicians’ low level of tolerance of uncertainty was found, with the respondents having a mean score of 22.53 (SD = 4.87), 64% of the maximum possible score of 35. The physician respondents perceived a high level of patient tolerance of diagnostic uncertainty, with less than half (45.57%) reporting a score higher than three. The mean score of patient tolerance of uncertainty was 3.82 (SD = 3.60), only 24% of the maximum possible score of 16  and less likely to prescribe antibiotics to patients with pneumonia . Physicians with higher diagnostic ability were less likely to prescribe antibiotics for patients with URTIs  and acute tonsillitis . In addition, for patients with acute tonsillitis, every one-unit increase in score of TFA (tolerance for ambiguity) (indicating a lower level of physician tolerance of uncertainty) showed a 9.8% increase in the odds of patients being prescribed with antibiotics  and every one-unit increase in score of patient AAM (Ambiguity Aversion in Medicine) (indicating a lower level of patient tolerance of uncertainty) showed a 34.3% increase in the odds of patients being prescribed with antibiotics , respectively (Table The logistic regression models showed that physicians with a higher perceived frequency of diagnostic uncertainty were more likely to prescribe antibiotics to patients with URTIs (adjusted odds ratio (AOR) = 1.034, p = 0.003) (Table p < 0.05). In contrast, when interacted with patients with low tolerance of uncertainty (scores ≥14), physician’s one-unit increase in score of TFA would further reduce the odds of antibiotic use . However, the marginal effect size remained low (up to 0.024). Combined with the effect of physician tolerance of uncertainty on antibiotic prescribing  Table . To show3) Table . When inup to 0.04. Combin15 and perverse incentives16 as the main drivers of the over-prescriptions of antibiotics in primary care physicians. The findings of this study contribute to the advancement of our understanding of such a complicated behavioural issue. The work of primary care physicians usually involves the treatment of illness conditions without a confirmed diagnosis, let alone a clear pathogen origin. Often, they have to make a clinical judgement and decision without further actions to clear the diagnostic uncertainty due to restrictions in time, technologies, and resources.This study offers some new insight into the antibiotic-prescribing behaviours of primary care physicians. Previous studies have identified insufficient knowledgeOur study shows that the physician perceived accumulated frequency of diagnostic uncertainty and diagnostic ability of primary care physicians are associated with antibiotic prescribing practices, albeit to varied degrees across illness conditions. Higher exposure to diagnostic uncertainty is associated with a higher level of antibiotic prescribing for URTIs, a condition where antibiotics are not recommended, but a lower level of antibiotic prescribing for pneumonia, a condition where antibiotics are recommended. In contrast, physicians’ and patients’ low perceived tolerances of uncertainty are associated with antibiotic prescribing for acute tonsillitis, a condition in which antibiotics are optional depending on the clinical judgement of prescribers.Clearly, diagnostic uncertainty is a significant barrier to implementing evidence-based practice guidelines. However, the certainty of recommendations in clinical guidelines may also influence the way in which the recommendations are adopted. It appears that the effect of physicians’ low tolerance of uncertainty varies with the instructions in the clinical guidelines. Physician low tolerance of uncertainty may have a limited effect, if any, on antibiotic prescribing for the conditions that antibiotics are unambiguously recommended or not recommended.18. However, this study also demonstrated that low tolerance of uncertainty was not significantly associated with antibiotic prescribing for URTIs or pneumonia, for which individual clinical judgement is virtually discouraged in the clinical guidelines. Esch and colleagues argued that physician and patient attitudes are particularly important in situations where antibiotic prescriptions are not clearly arbitrated in clinical guidelines3.The significant association between the low tolerance of uncertainty and increased antibiotic prescribing in primary care deserves increased research and policy attention. This study revealed that such an association is significant for acute tonsillitis, a condition that requires profound individual clinical judgement for antibiotic prescribing according to the clinical guidelines. Overall, the established link agrees with the results from several studies in which physician fear of uncertain consequences was found to have fuelled antibiotic prescriptions3. Physicians tend to change strategies in dealing with uncertainty when they perceive different levels of patient tolerance of uncertainty19. In the current study, we found that when interacted with different levels of patient tolerance of uncertainty, the effect of physician tolerance of uncertainty can go towards two different directions. Specifically, when interacted with patients with high tolerance of uncertainty, an increase in physicians’ scores in TFA (indicating a decrease of tolerance of uncertainty) would further increase the odds of antibiotic use. In contrast, when interacted with patients with low tolerance of uncertainty, an increase in physicians’ scores in TFA would further reduce the odds of antibiotic use . However, there is still space for further improvement.The overuse of antibiotics in primary care is still common in China despite great policy efforts in both restrictive and persuasive interventions. The average antibiotic prescribing rate per physician in this study ranged from 61% to 74% for different conditions, which represents a reduction of 20 percentage points compared to the level in 2009–2011  and lower use for pneumonia (antibiotics recommended). For acute tonsillitis, in which antibiotics should be cautiously used depending on the clinical judgement of prescribers, tolerance of uncertainty, rather than the frequency of diagnostic uncertainty, was associated with antibiotic-prescribing behaviours, with lower physician and patient tolerance of uncertainty resulting in a higher use of antibiotics. This study suggests that reducing diagnostic uncertainty as well as better physician and patient uncertainty management could reduce antibiotic use.This study adopted a cross-sectional design involving three main stages. First, a questionnaire survey of physicians was conducted to assess their characteristics relevant to diagnostic uncertainty. Second, physicians’ actual antibiotic-prescribing behaviours were evaluated based on their prescription data in three common diagnoses in primary care. Finally, we linked physician survey data with their prescription data to determine the association between factors relevant to diagnostic uncertainty and physician antibiotic-prescribing behaviour Fig. .26 and the USA6. Because these conditions have a varied likelihood of bacterial infection, antibiotics are not recommended for URTIs, the cautious use of antibiotics is applied for tonsillitis, and antibiotics are recommended for pneumonia. Considering that different diagnoses require varied decision making regarding antibiotic use, prescriptions and their prescribers were classified into three groups based on the three diagnoses. We separately analysed each group to determine the association between factors relevant to diagnostic uncertainty and physician antibiotic-prescribing behaviours.The three diagnoses included in the current study are URTIs, acute tonsillitis, and pneumonia with an unspecified organism, which were selected based on the national clinical guidelines for antimicrobial agents in China (2015 version)27.Two-stage cluster random sampling was adopted for the selection of primary care facilities in Hubei Province, China. In the first stage, the provincial capital, Wuhan, and the other four prefecture-level cities were randomly selected from the 16 cities in Hubei. In the next stage, five urban and five rural districts were further randomly selected in each included city. Within each district, all primary care facilities were included. This process resulted in 89 primary care facilities being included , which covered a geographic area with 6.55 million people According to the recommendation from the World Health Organization for a reliable estimate of physician antibiotic-prescribing patterns, physicians who issued at least 100 prescriptions for any one of the three selected diagnoses were eligible for the questionnaire survey. Based on the inclusion criteria, the sampling process generated a sample size of 469 eligible physicians from all included primary care facilities.Two steps were involved in data collection. The first step was a self-administered questionnaire survey of factors relevant to diagnostic uncertainty, collecting physician diagnostic ability, perceived frequency of diagnostic uncertainty, physician tolerance of uncertainty, and perceived patient tolerance of uncertainty. The second step was an assessment of the antibiotic-prescribing behaviours of these physicians based on their prescriptions in relation to the three selected illness conditions.In the first step, trained investigators were paired and deployed to the participating facilities to collect data from November 2019 to January 2020. Before the survey, all investigators had completed 1 day of intensive training, covering the background of the survey, a detailed explanation of the survey instrument, and a simulated survey test. The pairing of investigators aimed to help each investigator when one omitted some required procedures to ensure a standardized survey process.In total, 469 eligible physicians were invited to participate in this study. A total of 327 (69.72%) physicians returned a valid self-completed questionnaire.In the second step, prescriptions issued by the 327 questionnaire respondents were extracted from the 2018 outpatient prescription dataset gathered by the local governments. The International Classification of Diseases (ICD-10) codes J06.9 (URTIs), J03.9 (acute tonsillitis), and J18 (pneumonia with unspecified organism) were used to identify prescriptions for the three acute illness conditions. This resulted in a total of 207,804 prescriptions: 179,300 prescriptions for URTIs from 310 physicians; 21,347 prescriptions for acute tonsillitis from 53 physicians; and 7157 prescriptions for pneumonia from 24 physicians  of antibiotics  in each prescription served as the dependent variable.The independent variables contained two levels of measurements: prescription and physician levels. The prescription-level measurements included patient age, gender, and illness conditions embedded in the prescriptions. The physician-level measurements were captured by the questionnaire survey, which included sociodemographic characteristics of the physicians , and their perceived frequency of diagnostic uncertainty, diagnostic ability, tolerance of uncertainty, and patient tolerance of uncertainty.28 and defined diagnostic uncertainty as the “subjective perception of an inability to provide an accurate explanation of the patient’s health problem”. This resulted in the adoption of the common practices in existing studies in which factors relevant to diagnostic uncertainty were assessed based on physicians’ perception or estimation28.There is still no clear definition of what “diagnostic uncertainty” means and no comprehensive framework for its measurement in medical practice. Thus, we referred to a recent systematic review5. Respondents were asked to rate their experience on a five-point scale from 0–20% to 80–100%. Then, the reply was reserve coded with higher scores representing a higher frequency of diagnostic uncertainty (score 0: ≥80% patients were confidently given a clear diagnosis to score 3: <40% patients were confidently given a clear diagnosis).Physician perceived frequency of diagnostic uncertainty assessed the frequency with which physicians felt unable to provide a clear diagnosis to their patients. It was measured by one item: “in the past year for patients you prescribed antibiotics, about what percentage were you confident in giving a clear diagnosis?”, which has been validated in a previous study in the primary care setting29. Respondents were asked to identify one correct answer from five alternative options for each scenario. A summed score for each respondent was calculated, with a higher score indicating higher diagnostic ability.Diagnostic ability assessed the ability of physicians to correctly diagnose patient diseases based on five scenarios concerning influenza, bronchitis, pneumonia, pyelonephritis, and enteritis. These diseases were selected since they are the common reasons for the irrational use of antibiotics30. According to the TFA scale, respondents were asked to assess their attitudes towards statements relevant to uncertainty, for example, “before any important task, I must know how long it will take”. A six-point Likert scale was applied, ranging from 0 = “strongly disagree” to 5 = “strongly agree”, and the replies of all items were in the same direction; a higher score indicated a lower tolerance. A summed score for each respondent was calculated, with a higher score indicating a lower tolerance of uncertainty.Physician tolerance of uncertainty assessed physicians’ atttitudes towards uncertainty, which was measured by the seven-item TFA scale19. This scale measures the negative reactions of patients to diagnostic uncertainty, including (i) becoming unwilling to have the test or treatment, (ii) finding the information upsetting, (iii) becoming less trustful of medical experts, and (iv) losing confidence in the test or treatment. Respondents were asked to estimate the percentage of their patients holding negative reactions on a five-point Likert scale, ranging from 0 = “lower than 20%” to 4 = “higher than 80%”. The replies of all items are in the same direction that a higher score indicates a lower level of patient tolerance of uncertainty. A summed score was calculated for each respondent, with a higher score indicating a lower level of patient tolerance of uncertainty.Patient tolerance of uncertainty assessed patient attitudes towards diagnostic uncertainty, which was measured using the four-item AAM scaleThe above scales were tested in a pilot study of 24 primary care physicians, which demonstrated acceptable internal consistency with Cronbach’s alpha ranging from 0.69 to 0.84.The characteristics of the participating physicians and their patients for whom the prescriptions were issued were described through frequency analyses.18.A multivariate logistic regression model was established for each of the three illness conditions to determine the associations between factors relevant to the diagnostic uncertainty of physicians and their antibiotic-prescribing behaviours in primary care. The models were adjusted for variations in the demographic characteristics of patients (age and gender) and sociodemographic characteristics of physicians . These control variables were identified as potential predictors of antibiotic prescriptions in previous studies19. In the current study, the interaction term was introduced to the model because the prescribing behaviours of physicians varied with patient tolerance of uncertainty, and prescription decisions were considered a consensus between physicians and patients. To illustrate how the interaction influenced antibiotic prescribing, the plot of the marginal effect of the interaction between the two independent variables (physician tolerance of uncertainty × patient tolerance of uncertainty) on the dependent variable (antibiotic prescribing) was presented31.The regression models involved two levels, as the data were hierarchically structured with prescriptions nested in physicians. The two-level analyses allowed us to take into account the nested structure of the data and the differences in the number of patients per physician. Apart from the main effects of physician perceived frequency of diagnostic uncertainty, diagnostic ability, physician tolerance of uncertainty, and patient tolerance of uncertainty, the interaction effect between physician tolerance and patient tolerance of uncertainty on antibiotic prescribing was also tested in the models. According to existing studies, the main effect evaluates the relationship between independent variables and the dependent variable, while the interaction effect assesses the effect between the independent variables that impacts the dependent variablep < 0.05.All analyses were performed using STATA (version 14.0). The level of statistical significance was set at This study was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (No: 2020-S099). Written consent was obtained before the survey from each participant in the current study.Further information on research design is available in the Supplementary InformationReporting Summary


Escherichia coli varied considerably between individual practices, but the three prescribing groups’ means were very similar. However, as the higher-prescribing practices requested more urine cultures per 1000 registered patients, population resistance was markedly higher in the higher-prescribing groups. This study showed that the highly variable resistance percentages for individual practices were unrelated to antibiotic prescribing levels. However, population resistance (resistant strains per practice population) was related to antibiotic prescribing levels, which was shown to coincide with numbers of urine culture requests. Whether more urine culture requests in the higher-prescribing groups were related to treatment failures, more complex patient populations, or to general practitioners’ testing behaviour needs further investigation.A direct relation between antibiotic use and resistance has been shown at country level. We aim to investigate the association between antibiotic prescribing for patients from individual Dutch primary care practices and antibiotic resistance of bacterial isolates from routinely submitted urine samples from their patient populations. Practices’ antibiotic prescribing data were obtained from the Julius Network and related to numbers of registered patients. Practices were classified as low-, middle- or high-prescribers and from each group size-matching practices were chosen. Culture and susceptibility data from submitted urine samples were obtained from the microbiology laboratory. Percentages of resistant isolates, and resistant isolates per 1000 registered patients per year (population resistance) were calculated and compared between the groups. The percentages of resistant  Due to inappropriate antibiotic use, antimicrobial resistance (AMR) has become one of the most challenging problems in global health . AMR resEscherichia coli (E. coli) to amoxicillin, ciprofloxacin and trimethoprim of 38%, 10% and 23%, respectively, in urine cultures from adult patients [In Europe, primary care is responsible for prescribing 80 to 90% of antibiotics . Despitepatients . To our patients , and a sA driver for GPs to appropriate prescribing behaviour could be the awareness of higher levels of AMR in their practice population as compared to other practices, or to national figures . CurrentE. coli and other bacteria in urine isolates, routinely analysed from the practices’ populations. More robust information on a relation between antibiotic use and resistance in primary care would be highly relevant and useful in targeting interventions to appropriate antibiotic prescribing.In this study we therefore aim to explore the practice-level association between prescribed antibiotics and antibiotic susceptibility data of In 2017, the selected practices had a total of 96,926 registered patients, with population sizes ranging from 2559 to 13,655 patients. The low antibiotic-prescriber group had a total of 35,592 patients, the medium-prescriber 33,050 and the high-prescriber group had 28,284 patients. The high antibiotic-prescriber group contained smaller practices, and a non-significantly higher percentage of elderly patients . A totalp = 0.039). In total, 1466 E. coli (56%), 275 Klebsiella sp. (10.5%), 221 Enterococcus sp. (8.8%), 119 Proteus sp. (4.5%), and 63 Pseudomonas species (2.4%) were cultured. The prevalence of bacterial species differed slightly between the three groups. In high-prescriber practices, relatively more Pseudomonas and Proteus species and less E. coli were found.E. coli for the various antibiotics. Overall, there were notable differences between values for individual practices, with amoxicillin resistance varying between 27% and 62%, ciprofloxacin between 3% and 33%, and trimethoprim between 14% and 51%. This variation was apparent across prescriber groups and not related to prescribing levels, as comparable mean resistance percentages were found in the three prescriber groups, for example, around 40% for amoxicillin and between 35% and 37% for amoxi/clav.In total, 2628 isolates were tested for antibiotic sensitivity. E. coli to ciprofloxacin of 11% and to nitrofurantoin of 2% in the high-prescriber group.Relatively higher resistance to ciprofloxacin and nitrofurantoin was found in the high-prescriber group. One practice in that group showed very high resistance percentages to ciprofloxacin (33%) and nitrofurantoin (30%), which seemed to be related to patients with an indwelling urinary catheter. Removing this practice from the analysis resulted in a mean resistance of When relating the numbers of the resistant isolates from urine samples collected as part of routine primary care to the total number of isolates, a large practice variation was found, but without association with antibiotic prescribing levels. However, when resistant isolates were related to the number of registered patients in a practice (measured population resistance), a rising rate was found from low- to high-antibiotic prescribing practices.E. coli to amoxicillin (41% versus 38%), trimethoprim (27% versus 24%) and nitrofurantoin (3.5% versus 2%) than Nethmap data for 2017, whereas resistance to ciprofloxacin and fosfomycin were similar [In the Netherlands, Nethmap annually reports resistance percentages of isolates from routinely analysed urine samples. Our data from 2017 and 2018 indicate a slightly higher resistance of  similar .The complete dataset showed a five-fold difference in antibiotic prescribing between the lowest- and highest prescribing practices, which is consistent with other studies ,10,11. TE. coli and prior exposure to any antibiotic prescribed in primary care in the previous 12 months [Three other studies on the association between antibiotic use and AMR in primary care show conflicting results ,8,13. InThe strength of this study is the in-depth analysis of AMR in routinely collected urine samples from practice populations with highly variable antibiotic use, and relating resistance data to numbers of isolates, as well as numbers of registered patients. To our knowledge, such data linking has not been carried out before and, therefore, can be of use in the decision whether or not, and how, to use such data for feedback purposes.Several limitations should be acknowledged too. First, we used data on antibiotic prescribing, not dispensing or actual use, and have not included prescribing from other sources, like secondary care or dentists. We, however, assumed that correcting for these factors would not have a large impact on the variation in use as set by primary care prescribing. Second, in this retrospective population study with routine care data, we have not linked the individual’s antibiotic use to the microbiological data. The aim of our population-level study was not to investigate the individual’s risk of AMR from antibiotic use, which has been studied before ,15. ThirIn relating the resistance measured in routinely sent-in samples from primary care practices’ patient populations to the levels of antibiotic prescribing to those practices’ populations, one should be aware that using different denominators for resistance, the numbers of cultures, or the numbers of registered patients, can result in different conclusions. When expressed per number of cultures, the highly variable resistance percentages measured for individual practices were unrelated to their levels of antibiotic prescribing. It is, therefore, not advised to feedback these practice-based percentages in antibiotic surveillance and stewardship programs as a driver to appropriate antibiotic prescribing. Contrarily, when resistance was expressed per 1000 registered patients, this measure for population resistance seemed related to the level of antibiotic prescribing. More research is warranted to assess whether this relation indeed depends on differences in antibiotic use, or if it is confounded by the differences in patient populations and/or differences in policies for sending in urine samples for investigation.Setting: Numbers of prescribed antibiotics and numbers of registered patients per primary care practice were obtained from the Julius General Practitioners’ Network (JHN) database. This database contains routine healthcare data from digital patient records of 45 practices in Utrecht and its vicinity. This group of practices with their patient populations are a representative sample of the Dutch population . The datAntibiotic prescriptions: For 2017, JHN provided per practice the total numbers of prescribed systemic antibiotic courses, the numbers for each individual antibiotic subclass, of which amoxicillin, macrolides, amoxicillin/clavulanic acid (amoxi/clav), ciprofloxacin, nitrofurantoin and fosfomycin are shown in the results, and the total number of registered patients with subdivision into age groups, of which >65 and >80 years of age are shown.The numbers of antibiotic prescriptions/1000 registered patients/year were determined for each practice, resulting in a low prescribing quartile: <210 (low-prescribers), the middle two quartiles: 210–280 (medium-prescribers), and a high prescribing quartile: >280 courses/1000 registered patients/year (high-prescribers). From each quartile, 5 practices were chosen, matching with respect to patient population size. As it appeared that practices in the high-prescriber group had smaller patient populations, two additional practices were chosen in that group, resulting in a total of 17 practices. When prescribing data from 2018 became available, it appeared that the practices were still in the same prescribing quartile.Urine isolates: The JHN data manager decoded the 17 selected practices and communicated these to Saltro, the primary care microbiology laboratory. All selected primary care practices routinely sent their patients’ samples to this laboratory for culture and analysis. Urine samples were collected as part of normal primary care practice and analysed according to the standardised culture protocols of the laboratory.E. coli, therefore, cut-offs for resistance were: >0.5 mg/L for ciprofloxacin, >4 mg/L for trimethoprim/sulfamethoxazole (trimeth/sulfa) and trimethoprim, >8 mg/L for amoxicillin, amoxi/clav, and cefuroxime, >32 mg/L for fosfomycin and >64 mg/L for nitrofurantoin. Cut-offs for the other species–antibiotics combinations can be found in the EUCAST standard [From the 17 practices, the urine culture microbiological data of 2017 and 2018 of all sent-in samples of patients belonging to these practices were retrieved from the Saltro database. Saltro classified isolates as susceptible, susceptible-increased-exposure, or resistant according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) versions 7.1 to 8.1 . For thestandard . Each prThe JHN data manager transferred these sets with the same practice codes as the prescribing data, enabling the linking of practice antibiotic prescribing to resistance data.E. coli, Klebsiella-, Enterococcus-, Proteus-, Pseudomonas species and all others species combined.The three prescriber groups were compared with respect to the following practice variables: numbers of registered patients, percentages of elderly (>65 and >80 years of age), numbers of prescribed antibiotic subgroups /1000 patients/year, numbers of urine culture requests/1000 registered patients/year and percentages of cultivated bacteria: E. coli isolates, as this is the most frequently cultured species from urinary tract infections and because the wild type is without intrinsic resistance to the antibiotics under study [To evaluate a possible relation between practice antibiotic prescribing and measured AMR in their patient population, for each practice numbers of isolates resistant to amoxicillin, amoxi/clav, cefuroxime, ciprofloxacin, trimeth/sulfa, trimethoprim, fosfomycin and nitrofurantoin were determined. Susceptibility to these particular antibiotics and some additional ones is routinely analysed in the laboratory , and theer study ,20,21. Ap-value <0.05 was considered statistically significant.Results are presented as means, with lowest and highest group values, and as percentages. Differences between the three prescriber groups were tested using one-way ANOVA. Post-hoc Bonferroni multiple comparison testing was used to determine which groups differ statistically from others. A The answer whether antibiotic use is related to antimicrobial resistance at the level of individual primary care practices seems to depend on the denominator of resistance. Resistance percentages per number of urine cultures were not related to antibiotic prescribing levels. However, resistance per practice population was related to levels of antibiotic prescribing, therefore, the known association between antibiotic use and resistance at country level was also found at the micro-level of individual primary care practices.


ERBB2-positive breast cancer.This economic evaluation modeled the cost-effectiveness of 5 neoadjuvant-adjuvant treatment strategies for women with  ERBB2-positive breast cancer in the United States?What is the cost-effective neoadjuvant-adjuvant treatment strategy among several clinically reasonable alternatives for human In this economic evaluation, based on the KATHERINE trial and other clinical trials and evidence sources, neoadjuvant trastuzumab plus paclitaxel plus pertuzumab followed by adjuvant trastuzumab for patients with pathologic complete response or followed by adjuvant dose-dense anthracycline/cyclophosphamide and trastuzumab emtansine for patients with residual disease was associated with the highest health benefits and least costs among 5 strategies considered.These findings suggest that, among 5 neoadjuvant-adjuvant treatment strategies, 1 strategy is associated with not only improved health outcomes but also cost savings. ERBB2-positive  breast cancer are associated with different rates of pathologic complete response (pCR). The KATHERINE trial showed that adjuvant trastuzumab emtansine (T-DM1) can reduce recurrence in patients with residual disease compared with patients treated with trastuzumab; however, T-DM1 and other ERBB2-targeted agents are costly, and understanding the costs and health consequences of various combinations of neoadjuvant followed by adjuvant treatments in the United States is needed.The neoadjuvant treatment options for ERBB2-positive breast cancer.To examine the costs and disease outcomes associated with selection of various neoadjuvant followed by adjuvant treatment strategies for patients with ERBB2-positive breast cancer from a health care payer perspective in the United States. The model was informed by the KATHERINE trial, other clinical trials with different regimens from the KATHERINE trial, the Flatiron Health Database, McKesson Corporation data, and other evidence in the published literature. Starting trial median age for KATHERINE patients was 49 years . The model simulated patients receiving 5 different neoadjuvant followed by adjuvant treatment strategies. Data analyses were performed from March 2019 to August 2020.In this economic evaluation, a decision-analytic model was developed to evaluate various neoadjuvant followed by adjuvant treatment strategies for women with There were 4 neoadjuvant regimens: (1) HP: trastuzumab (H) plus pertuzumab (P), (2) THP: paclitaxel (T) plus H plus P, (3) DDAC-THP: dose-dense anthracycline/cyclophosphamide (DDAC) plus THP, (4) TCHP: docetaxel (T) plus carboplatin (C) plus HP. All patients with pCR, regardless of neoadjuvant regimen, received adjuvant H. Patients with residual disease received different adjuvant therapies depending on the neoadjuvant regimen according to the 5 following strategies: (1) neoadjuvant DDAC-THP followed by adjuvant H, (2) neoadjuvant DDAC-THP followed by adjuvant T-DM1, (3) neoadjuvant THP followed by adjuvant DDAC plus T-DM1, (4) neoadjuvant HP followed by adjuvant DDAC/THP plus T-DM1, or (5) neoadjuvant TCHP followed by adjuvant T-DM1.Lifetime costs in 2020 US dollars and quality-adjusted life-years (QALYs) were estimated for each treatment strategy, and incremental cost-effectiveness ratios were estimated. A strategy was classified as dominated if it was associated with fewer QALYs at higher costs than the alternative.In the base-case analysis, costs ranged from $415 833 (strategy 3) to $518 859 (strategy 4), and QALYs ranged from 9.67 (strategy 1) to 10.73 (strategy 3). Strategy 3 was associated with the highest health benefits (10.73 QALYs) and lowest costs ($415 833) and dominated all other strategies. Probabilistic analysis confirmed that this strategy had the highest probability of cost-effectiveness  and was associated with the highest net benefit.ERBB2-positive breast cancer compared with other treatment strategies considered.These results suggest that neoadjuvant THP followed by adjuvant H for patients with pCR or followed by adjuvant DDAC plus T-DM1 for patients with residual disease was associated with the highest health benefits and lowest costs for women with  ERBB2 –targeted agents is increasingly used in the treatment of stage II to III ERBB2-positive breast cancer because this treatment strategy can lead to increased breast conservation and smaller resection volumes1 and the extent of residual cancer can guide subsequent postoperative  treatment.2 Patients with pathologic complete response (pCR), defined as no residual invasive cancer in the breast or lymph nodes , have excellent overall survival rates, regardless of neoadjuvant chemotherapy regimen used.4 Rates of pCR range from 6% to 80% in ERBB2-positive breast cancer, depending on regimen and estrogen receptor (ER) status. Trastuzumab and pertuzumab without any chemotherapy can result in 6% pCR rate in ER-positive/ERBB2-positive cancers,5 whereas the combination of trastuzumab and pertuzumab with sequential anthracycline and taxane chemotherapy can result in pCR rates as high as 80% in ER-negative/ERBB2-positive cancers.7 Equally importantly, the decreased survival rates of patients with residual ERBB2-positive disease compared with individuals with pCR can be improved by additional, adjuvant therapy with trastuzumab emtansine (T-DM1). The KATHERINE trial8 compared adjuvant T-DM1 with adjuvant trastuzumab in patients who had residual disease after neoadjuvant chemotherapy and ERBB2-targeted therapy. Of 1486 patients included in the trial , all received a taxane, 1143 individuals (77%) received an anthracycline in the neoadjuvant setting, and 290 individuals (20%) received dual ERBB2-targeted therapy  concurrent with chemotherapy. The trial showed significantly improved invasive disease–free survival  and distant metastasis–free survival  with T-DM1.8 In a similar trial in individuals with ERBB2-negative breast cancer, adjuvant capecitabine improved disease-free and overall survivals in patients with residual disease after neoadjuvant chemotherapy that contained anthracycline, taxane, or both.9 These randomized clinical trials in different disease subtypes demonstrated the clinical principle that further adjuvant chemotherapy for patients with residual disease after neoadjuvant chemotherapy can improve outcome.Preoperative  chemotherapy in combination with ERBB2-positive breast cancer, there are several neoadjuvant chemotherapy options, each associated with different costs, toxic effects, and rates of pCR. This study examined the cost-effectiveness of different neoadjuvant-adjuvant treatment strategies in the United States. We assume that (1) breaking up a sequential, multidrug regimen into preoperative and postoperative components will result in the same overall outcome as administering all treatment preoperatively,10 (2) patients who achieve pCR will have similarly good prognosis regardless of what regimen, or regimen component, induced pCR,11 and (3) patients with the same residual disease amount have similar prognosis, regardless of type of neoadjuvant regimen. We based our decision-analytic model on the KATHERINE trial population and outcome and on data from other clinical trials for regimens that were not used in that trial.For CHEERS) reporting guideline12 and using R statistical software version 3.6.2 .13 The decision tree included 5 different neoadjuvant-adjuvant treatment strategies and distributed patients into 1 of the Markov models  in US settings. The model considered 4 neoadjuvant regimens: (1) HP: trastuzumab (H) and pertuzumab (P); (2) THP: paclitaxel (T), H, and P; (3) DDAC/THP: dose-dense anthracycline/cyclophosphamide (DDAC) followed by THP; and (4) TCHP: docetaxel, carboplatin, H, and P. Patients with pCR after any of these neoadjuvant regimens received H in the adjuvant setting. Patients with residual disease received adjuvant therapies depending on their prior neoadjuvant therapy, resulting in 5 overall neoadjuvant-adjuvant treatment strategies: (1) neoadjuvant DDAC/THP followed by adjuvant H for patients with pCR or residual disease, (2) neoadjuvant DDAC/THP followed by adjuvant T-DM1 for patients with residual disease and followed by adjuvant H for patients with pathological CR, (3) neoadjuvant THP followed by adjuvant DDAC followed by T-DM1 for patients with residual disease (similar to the KATHERINE neoadjuvant regimen but split into preoperative and postoperative components) and followed by adjuvant H for patients with pathological CR, (4) neoadjuvant HP (a nonchemotherapy neoadjuvant regimen) followed by adjuvant DDAC/THP plus T-DM1 for patients with residual disease and followed by adjuvant H for patients with pathological CR, and (5) neoadjuvant TCHP followed by adjuvant T-DM1 for patients with residual disease and followed by adjuvant H for patients with pathological complete response .15 The model also accounted for chemotherapy toxic effects with 2 additional health states: acute myeloid leukemia and congestive heart failure (CHF). Death state included breast cancer–related, acute myeloid leukemia–related, CHF-related, and age-dependent other-cause death.The Markov model with 4 main health states  simulated lifetime costs and quality-adjusted life-years (QALYs) associated with neoadjuvant-adjuvant regimen combinations, applying a 3% discounting rate .15 The m38 and were 16.8% for HP, 45.8% for THP, 56.5% for DDAC/THP, and 52.5% for TCHP  of distant recurrence: T-DM1: 0.60; DDAC/THP followed by T-DM1: 0.52; and DDAC followed by T-DM1: 0.408 .33We estimated patients’ quality of life by assigning different utility weights to each health state taken from published literature .20,21,22dominated if it was associated with fewer QALYs at higher costs than the alternative. We classified a strategy as cost-effective if it was associated with the highest ICER below the willingness-to-pay threshold considered. If 1 strategy was associated with the most QALYs and lowest costs compared with all other strategies, we classified it as optimal. In our cost-effectiveness evaluation, we considered 3 recommended willingness-to-pay thresholds of $50 000/QALY, $100 000/QALY, and $150 000/QALY.40The main outcomes of the decision-analytic model were costs and QALYs associated with each treatment strategy. We first ranked the 5 strategies by their costs, then estimated incremental costs and incremental QALYs, and then calculated incremental cost-effectiveness ratios (ICERs). ICER represents incremental costs per QALY gained relative to the next least-costly strategy. We classified a strategy as 41 and for patients with various amounts of residual disease, we used probabilities of distant recurrence as reported in the KATHERINE trial  and ER-negative cancers  compared with the total population .8 Consequently, the results of these subgroups analyses and the base-case results may not be directly comparable.We also performed 2 subgroup analyses that evaluated cost-effectiveness of treatment strategies in patients stratified by ER status of their cancer . In these subgroup analyses, we used ER-specific rates of pCR for each neoadjuvant treatment regimen,probabilistic sensitivity analysis, with 1000 iterations to propagate parameter uncertainty to the model output. We evaluated the probability that a given strategy was cost effective using cost-effectiveness acceptability curves and the probability that the strategy associated with the highest net benefit was cost effective using a cost-effectiveness acceptability frontier for willingness-to-pay thresholds from $0 to $200 000/QALY. Furthermore, we examined uncertainty in the results of our model with 1-way sensitivity analyses varying base-case values of the influential parameters (1 at a time) by increases and decreases of up to 30%. These parameters included rates of pCR after each neoadjuvant treatment, distant recurrence risk in patients with residual disease receiving different adjuvant treatments, probability of CHF and acute myeloid leukemia , and costs of distant recurrence health state. Additionally, we conducted a scenario analysis that added adjuvant P to adjuvant H in patients with pCR. We performed all analyses using R statistical software version 3.6.2 .13 Data analyses were performed from March 2019 to August 2020.We assigned a probability distribution to each input parameter and conducted a probabilistic analysis, also known as Strategy 3 was associated with the highest health benefits (10.73 QALYs) at the lowest costs ($415 833) compared with all other strategies. This strategy dominated all other treatment strategies and was deemed the optimal strategy . All othIn patients with ER-positive cancer, strategy 3 was associated with 10.59 QALYs and the least costs, at $433 411, and represented a cost-effective strategy at the 3 willingness-to-pay thresholds . In thesIn probabilistic analysis, strategy 3 was associated with the highest probability of cost-effectiveness compared with other strategies  and was associated with the highest net monetary benefit across all willingness-to-pay thresholds, from $0 to 200 000/QALY . These fERBB2-positive breast cancer by modeling our patient population and outcomes based on the KATHERINE trial. This economic evaluation found that neoadjuvant THP followed by adjuvant DDAC and T-DM1 for individuals with residual disease and followed by adjuvant H for individuals with pCR  was the optimal strategy as it was associated with the greatest health benefits and lowest costs compared with other considered treatment strategies. In our results stratified by ER status, strategy 3 was the cost-effective strategy for treating patients with ER-positive or ER-negative cancers using the 3 willingness-to-pay thresholds. In sensitivity analyses that varied pCR rate and recurrence risks with residual disease, strategy 3 remained the optimal strategy or was the cost-effective strategy.We performed a model-based economic evaluation that examined the cost-effectiveness of 5 neoadjuvant followed by adjuvant treatment strategies for ERBB2-positive cancers. A crucial recent development was the recognition that adjuvant chemotherapy can improve the survival of patients who do not achieve pCR.9 There is also mounting evidence that pCR is associated with similarly good survival regardless of what chemotherapy regimen is administered.43 These observations open the opportunity for de-escalation of neoadjuvant chemotherapy and the use of the presence or absence of residual disease to guide subsequent postoperative adjuvant chemotherapy. Starting with a shorter, less toxic, and less expensive neoadjuvant regimen may allow a proportion of patients (20%-40% depending on regimen) who achieve pCR to avoid longer, more toxic regimens, whereas patients with residual disease may be able to receive the remaining part of the most effective current regimens postoperatively as adjuvant therapy.Pathologic complete response is associated with long-term metastasis-free survival, and maximizing rates of pCR was an important goal of clinical trials in the past 20 years. This has been associated with the development of longer, more toxic, and more costly multidrug regimens for 17Providing patients with neoadjuvant treatment associated with decreased rates of pCR  may be associated with decreased neoadjuvant treatment costs. However, it may also be associated with increased adjuvant treatment costs due to patients with residual disease receiving more costly adjuvant treatment when they would have achieved pCR with TCHP. Our model estimates total costs associated with each neoadjuvant-adjuvant treatment strategy, accounting for neoadjuvant and adjuvant treatment costs and simulated health states. We also realize that selecting a treatment strategy involves personal trade-offs. For example, neoadjuvant THP spares many patients (approximately 46%) from receiving adjuvant chemotherapy, but an estimated 7% to 11% of patients with residual disease after THP will receive more chemotherapy  than they would have received if they started by receiving neoadjuvant TCHP or DDAC-THP. These are the 7% to 11% of patients who would have had pCR with the more aggressive initial neoadjuvant therapy.ERBB2-positive breast cancer. A 2020 study44 evaluated the cost-effectiveness of breast cancer treatments but focused on the neoadjuvant setting. That study’s results should not be directly compared with ours, because the treatment strategies differed between the 2 studies. However, we compared the cost-effectiveness results for the treatment strategies that were similar in the 2 studies, and our results were in line with the previous results, indicating that THP represented the preferred neoadjuvant treatment.44 Unlike the previous study, our study provided results for various neoadjuvant-adjuvant treatment combinations, where the adjuvant treatment was chosen depending on the provided neoadjuvant treatment.To our knowledge, this is the first study to examine the cost-effectiveness of different combinations of neoadjuvant followed by adjuvant treatment strategies for women with P = .045) compared with trastuzumab alone.45 However, to our knowledge, there are no studies on how adjuvant pertuzumab added to trastuzumab may change the distant recurrence risk in patients with residual disease after neoadjuvant therapy, including neoadjuvant regimens with pertuzumab. Similarly, the ExteNET (Extended Adjuvant Treatment of Breast Cancer With Neratinib) trial46 showed that adjuvant neratinib given after adjuvant trastuzumab improved invasive disease-free survival, from 88% to 90% (P = .008), compared with placebo, but there are no studies, to our knowledge, on how adjuvant neratinib may alter outcomes in patients with residual disease after neoadjuvant, ERBB2-targeted therapy. It is possible that adjuvant pertuzumab and neratinib may improve prognosis among patients with residual disease regardless of T-DM1 administration, but the magnitude of this improvement, if any, is unknown. Our sensitivity analysis suggested that our results may hold up in patient populations with broad ranges of recurrence risk.This study has several limitations. Owing to lack of outcome data from clinical trials, we did not consider additional clinically plausible adjuvant treatment regimens. For example, adjuvant pertuzumab added to trastuzumab increased the 3-year invasive disease-free survival rate from 91% to 93% (47 which compared neoadjuvant anthracycline/cyclophosphamide (AC) followed by adjuvant docetaxel with neoadjuvant AC plus docetaxel, and the long-term survival was the same in both docetaxel-containing arms, regardless of administration sequence . A clinical trial ,48 with estimated start date of January 2021, will prospectively test de-escalation strategies using THP as neoadjuvant therapy and reserving further treatment for individuals with residual disease.There are no randomized clinical trial data, to our knowledge, demonstrating that neoadjuvant THP followed by adjuvant DDAC and T-DM1 for patients with residual disease results in the same long-term outcomes as neoadjuvant THP-DDAC followed by T-DM1 for patients with residual disease, which is a fundamental premise behind our model. Nevertheless, we believe that this is a reasonable assumption based on the National Surgical Adjuvant Breast and Bowel Project Protocol B-27 (NSABP-B-27) trial,ERBB2-positive  cancer, like the KATHERINE trial population, neoadjuvant THP followed by adjuvant DDAC and T-DM1 for patients with residual disease and followed by H for patients with pCR is associated with the highest health benefits and lowest costs compared with other treatment regimens. This treatment regimen seems to represent the preferred strategy in ER-positive and ER-negative cancers.These findings suggest that, in a patient population with


It is commonly recommended that microbiological assessment should accompany the use of antibiotics prone to resistance. We sought to estimate the rate of microbiology testing and compare this to dispensing of the World Health Organization classified “watch” group antibiotics in primary care.Data from a cohort of older adults (mean age 69 years) were linked to Australian national health insurance  records of community-based antibiotic dispensing and microbiology testing in 2015. Participant characteristics associated with greater watch group antibiotic dispensing and microbiology testing were estimated using adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) in multivariable zero-inflated negative binomial regression models.In 2015, among 244,299 participants, there were 63,306 watch group antibiotic prescriptions dispensed and 149,182 microbiology tests conducted; the incidence rate was 0.26 per person-year for watch group antibiotic dispensing and 0.62 for microbiology testing. Of those antibiotic prescriptions, only 19% were accompanied by microbiology testing within − 14 to + 7 days. After adjusting for socio-demographic factors and co-morbidities, individuals with chronic respiratory diseases were more likely to receive watch group antibiotics than those without, e.g. asthma  and chronic obstructive pulmonary disease (COPD) . However, the rate of microbiology testing was not comparably higher among them .Priority antibiotics with high resistance risk are commonly dispensed among community-dwelling older adults. The discord between the rate of microbiology testing and antibiotic dispensing in adults with chronic respiratory diseases suggests the potential for excessive empirical prescribing. Antibiotic resistance is a severe threat to global public health. It is estimated that each year infections caused by antibiotic-resistant pathogens result in 700,000 deaths worldwide; the number might reach 10 million in 2050 if there is no effective action to curb resistance . To guidStreptococcus pneumoniae resistance [Escherichia coli resistance [Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), were also reported to be associated with the use of quinolines and extended-spectrum cephalosporins [Earlier epidemiological studies and surveillance programs, nationwide and worldwide, have reported the use of some classes of watch/reserve group antibiotics and their relationship with antibiotic resistance in the population, e.g. the use of macrolides and sistance , 12, andsistance –13. Someosporins , 15. Howhttps://www.saxinstitute.org.au/our-work/45-up-study/questionnaires/). They also agreed to have their questionnaire information linked to their health records. In this study, we linked the cohort to the Pharmaceutical Benefits Scheme (PBS), Medicare Benefits Schedule (MBS) based on a unique identifier provided by the DHS, and the NSW Admitted Patient Data Collection (APDC), and the NSW Registry of Births, Deaths and Marriages (RBDM) database through probabilistic linkage by the NSW Centre for Health Record Linkage (CHeReL).We used the Sax Institute’s 45 and Up Study, a large-scale cohort which recruited 267,153 participants aged ≥45 years from 2006 to 2009 in the largest Australian state, New South Wales (NSW). Participants were randomly sampled from the Department of Human Services (DHS) enrolment database. Detailed information on the cohort has been published previously . ApproxiThe PBS database records medicines dispensed for outpatients subsidized by the Australian government pharmaceutical scheme; data include the dates of dispensing, medicine names, and WHO Anatomical Therapeutic Chemical (ATC) codes. About 98% of recorded antibiotic prescriptions in the PBS database were supplied from community pharmacies; others were supplied from private hospitals or other healthcare facilities . The MBSThe study was approved by the University of New South Wales Human Research Ethics Committee (number 10186), and the NSW Population and Health Services Research Ethics Committee (HREC/10/CIPHS/97).Our primary outcome was the number of watch and reserve group systemic antibiotic prescriptions dispensed to each cohort participant recorded in the PBS database from 1st January 2015 to 31st December 2015 (observation period). The list of antibiotics classified as watch/reserve group is shown in Supplementary Table A secondary outcome was the number of microbiology tests for bacterial infections received by each participant during 2015 based on records in the MBS database (see Supplementary Table Socio-demographic factors for each participant were derived from the 45 and Up Study baseline questionnaire. We included sex (men or women), age-group in 2015 , education , annual household income at baseline in Australian dollars , and residential area . Missing values in each covariate were included as a separate group.The primary patient subgroups of interest in our study were those with major chronic diseases and those living in LTCF. We derived co-morbidities and other health service use from the MBS and APDC databases. For participants who were dispensed watch/reserve group antibiotics during 2015, an index date was defined as the first date of watch/reserve group antibiotic dispensing; for participants who were not provided watch/reserve group antibiotics, the index date would be 9th July 2015, the median date of watch/reserve group antibiotic dispensing among participants. Residence in a LTCF was ascertained if participants had an MBS record of a medical service in a LTCF  and calculated 95% confidence intervals (CI) to identify the associations of major comorbidity and residence in LTCF with watch/reserve group antibiotic dispensing and microbiology testing. We also assessed risk factors for the dispensing of macrolides , other We also examined the timing of microbiology tests in relation to the dispensing of watch/reserve group antibiotics. We calculated the proportion of watch/reserve group antibiotic prescriptions that had an accompanying microbiology test performed within 14 days prior to or 7 days after the dispensing date for study populations, considering that the tests performed around the day of dispensing are potentially related to the antibiotic treatment.P value< 0.05 was used as the threshold for statistical significance.All analyses were conducted using Stata version 14.1. Two-sided After excluding people who died before 2015, we included 244,299 individuals (mean age 69 years) of whom 120,747 (49%) were dispensed ≥1 antibiotic prescription in 2015. Among those 120,747 participants, a total of 403,492 antibiotic prescriptions were dispensed, of which 63,306 (16%) were watch/reserve group antibiotics. There were 29,917 (12%) participants who were dispensed at least one watch/reserve group antibiotic prescription: 13,914 (5.7%) were dispensed one; 10,102 (4.1%) were dispensed two; and 5901 (2.4%) were dispensed three or more prescriptions. There were fewer than five reserve group antibiotic prescriptions; thus, they were included in the watch group analyses; and in the following text, we simply refer to the group as watch group. As shown in Table In 2015, the incidence rate was 0.26 per person-year for watch group antibiotic dispensing and 0.62 per person-year for microbiology testing , but no increase in microbiology testing (P = 0.161), which is consistent with the main analysis.Given the strong association of chronic respiratory diseases with watch group antibiotic dispensing, we further examined the relationships according to disease severity  . This isWatch group antibiotics are commonly dispensed among older adults in the community. This is particularly true for patients with asthma and COPD; however, their likelihood of receiving microbiology testing is not comparably high, indicating the potential for excessive empirical watch group antibiotic use. Since watch group antibiotics have high resistance potential, focusing antibiotic stewardship efforts might be needed among older populations with chronic respiratory diseases in the primary care setting.Additional File 1 Table S1. Classification for watch group and reserve group according to the WHO Model List of Essential MedicinesAdditional File 2 Table S2. Medicare Benefits Schedule (MBS) codes used for GP consultations, aged care facilities  attendance and microbiology testingAdditional File 3 Table S3. Incidence rate ratio for watch group antibiotic dispensing and microbiology testing by participants’ characteristicsAdditional File 4 Table S4. Incidence and incidence rate ratio for dispensed amoxicillin-clavulanate prescriptions by participants’ characteristicsAdditional File 5 Table S5. Incidence and incidence rate ratio for dispensed watch group antibiotic prescriptions without antibiotic use in the 14 days prior to dispensing by participants’ characteristicsAdditional File 6 Table S6. Incidence rate ratio for dispensed macrolides and other watch group antibiotics prescriptions by participants’ characteristicsAdditional File 7 Table S7. Incidence rate ratio for certain types of microbiology testing among 244,299 participants by participants’ characteristicsAdditional File 8 Table S8. Incidence of dispensed antibiotic prescriptions and microbiology tests and their association between chronic lower respiratory tract diseasesAdditional File 9 Figure S1. The distribution of the intervals between dispensed script of watch group antibiotics and its closest microbiology test .