The development of a wireless link for biomedical applications requires an accurate estimation of the delivered power to implanted devices. In particular, a variety of mid-range applications in the biomedical area have gained significant attention. An appropriate method for the mid-range wireless link is required to implement a continuous wireless link through human tissue. Even though formulas used in this work are all based on previous works, this paper presents an implementation of the diverse formulas for the mid-range wireless link of an implanted antenna used for a pacemaker system based on the understanding on radiation properties varied with the distances from the antenna. The formulas based on input far-field data are successfully applied to compute the power transmission for the implanted devices, whose range includes radiative near-field and far-field regions. The wireless link for a pacemaker system is evaluated through using a patch antenna immersed with different depths of human tissue. A comparison of the computed and measured results shows an excellent agreement where the validity of the evaluation is demonstrated.  The use of implantable medical devices (IMD) has led to the advancement of various medical treatments and diagnostic methodologies. In particular, pacemakers have received a considerable amount of interest for the patients suffering from abnormal heart rhythms. They have been used to successfully recover heart rhythms for the patients. The implantable medical devices, such as pacemakers, typically require wireless power transfer (WPT) as well as wireless data transfer . The useIn this paper, the radiation characteristics around the implanted antenna are studied, and several techniques based on the far-field radiation characteristics are revisited and its applications to the wireless link for the implanted antennas are presented. The mid-range radiation characteristics are studied through the near-field distribution where the antenna is immersed with different depths of human tissue for pacemaker application. In the following section, the phenomenon of the reduction in the far-field gain, known as “gain reduction factor”, is used to describe the radiation characteristics in the radiative near-field region. This work provides an overview of important features for the several techniques used in the mid-range wireless link: (i) asymptotic Friis formula, (ii) Chu formula, and (iii) integral coupling formula. The detailed procedure to obtain the wireless link is discussed, and the formulas are applied to the various cases of the biomedical wireless link. In order to include all near-field wireless links, this work revisits the two-port network for the investigation of inductive coupling where the wireless link is made in a reactive near-field region.The derivation of the related formulas, applications, and measurements have been profoundly discussed in ,35,36,37The radiation characteristics can be varied from the near-field region to the far-field region of the antenna of interest. There are two categories in the near-field region: reactive near-field region and radiative near-field region. The reactive near-field region is known as non-radiative near-field region or inductive near-field region. The boundary to distinguish reactive near-field from radiative near-field is known as  antenna . This paD2/λ or 2λG/π2 [G and FG are the far-field gain and Fresnel gain of the antenna, respectively, and the coefficient α is related to the rate of the reduction in the far-field gain G, which is found to be α = 0.066. The normalized distance Δ can be defined asented in  can be dr 2λG/π2 . The difIn this paper, the gain reduction factor with the proposed separation distance integrated with the Friis formula is used to enhance the accuracy in the radiative near-field region.This subsection presents appropriate methods for calculating the mid-range wireless link and important features of the different techniques. Three different methods used in the evaluation include (i) asymptotic Friis formula, (ii) Chu formula, and (iii) integral coupling formula. The first two formulas based on the far-field gain are advantageous in providing an almost instant calculation. However, the drawbacks include the limitation of the possible scenarios and the slight loss of the effective range, compared to other methods. The integral coupling formula utilizes the FFT of the far-field data with magnitude and phase. Even though relatively complex far-field data are required, the applications of the formula, including various case studies, are very wide. The three different methods are all accurate and time-efficient, even when not taking the recent advancement of computing capabilities into consideration. R is the separation distance between two antennas. t and r represent the transmitting and receiving antenna, respectively. Although it predicts well in the far-field region, a comparison between the Friis formula and measurements imply that the Friis formula is inaccurate in a short distance [R and far-field distance 2D2/λ, has been used to include the gain reduction effect in the radiative near-field region. The problem of the formula is the intense computation of the gain reduction factor required for each antenna. It has been found in [The Friis formula, derived from plane-wave characteristics, has been widely used for the long-range wave propagations . A confidistance ,29. The F(G) is incorporated with the gain reduction factor In order to include both cases of low and high gain antennas, the switching function a = 3, b = 5, and c = 1, are selected for smooth switching. The other technique based on the Gaussian beam has been applied to both the radiative near-field region and far-field region. It is worth noting that tG and rG included in the correction term are substituted with the directivity of the transmitting and receiving antenna, respectively. In this work, the parameters, R and effective aperture area eA, which is also relevant to the far-field gain G. The Gaussian beam is used to include both approximation in the far-field region and gain reduction effect in the radiative near-field region.An approximation of the Friis formula has been derived based on the fundamental mode of Gaussian beams, which is called “Chu formula”. The formula is a function of the distance F(G) is incorporated with the antenna gain in the correction term, except for the Friis formula. In contrast to the separable asymptotic gain reduction factors for transmitting and receiving antennas, the formula includes a combined form of the gain reduction factors of the two antennas. It is worth noting that the switching function In the formula, a fast Fourier transform (FFT) has been used to obtain the near-field coupling from both the magnitude and phase of the far-field pattern ,35,36,37ented in  can be dWith an effort to extend the effective range, it is demonstrated that the far-field approximation to the integral coupling is well converged into the Friis formula. A valid range of the integral coupling, therefore, includes radiating both the near-field region and far-field region.The radiation characteristics of an antenna inside the human tissue are studied through the near-field distribution, where the antenna is immersed with different depths of human tissue for the pacemaker application. In the following subsection, the phenomenon of the reduction in the far-field gain, known as “gain reduction factor”, is used to describe the radiation characteristics in the radiative near-field region. Based on the understanding of the gain reduction factors, the related formulas are presented to predict the power transmission made in the radiative near-field region. rε = 10.2. The size of the reader patch is 40 cm × 40 cm, which is printed on 3.4 mm thick substrates with rε = 2.2. As shown in R between the implanted antenna and the measured points. The radiation patterns, changed from the flat radiative pattern to the directive far-field radiation pattern, are described. The radiation patterns are obtained with different thicknesses of the human tissue, which are set as 4 mm and 8 mm. Since the thickness of the human tissue is comparable to the distance R for the case of small R, the distance R is measured as the wavelength in the air, λ0 and the one in skin tissue, λe. The broadside gains at the different positions are used to derive the curve of the gain reduction factor. The gain reduction factor is obtained using the asymptotic formula presented in [F(G). It is observed that the gain reduction for the case of the reader patch antenna is greater than the other case of the implanted antenna. It is attributed to the fact that the gain reduction factor with the higher far-field gain typically produces the larger reduction in the antenna gain at the same distance R.A useful representation of the reduced antenna gain in the radiative near-field region is the gain reduction factor. The effects of the significant decrease in the near-field power transmission indicate that the reduction in antenna gain exists in a proximity distance. The near-field distribution of a patch antenna inside the human tissue is presented to examine the gain reduction effect of the biomedical devices. The radiation characteristics are investigated for the patch antenna immersed with different depths of the human tissue, whose specification was presented in . The sizented in . The modented in . The modλ, the gain reduction factor rapidly decreases due to the failure of the quadratic form of gain reduction factor in the close proximity. The power transmission based on the gain reduction factor is investigated in the following subsection.A comparison between calculated and simulated gain reduction factors is provided in The main purpose of this section is to examine the power transmission to the implanted antennas for the pacemaker application. A variety of formulas discussed in the previous section are applied to the case of the near-field and the far-field wireless link. Based on the discussion of the radiation characteristics for different positions, biomedical applications of the formulas are provided in this section. The formulas have been applied to the on-axis and rotational scenarios which are commonly used in biomedical applications.z-axis. The far-field gains and directivities applied to the formulas are provided in λ, since the gain reduction factor is starting to decrease rapidly, as discussed in The integral coupling formula has been used to successfully evaluate the biomedical wireless link presented in . The useThe applicability of the formulas is examined for the case of the rotational scenario. The power transmission is evaluated for the case in which the implanted antenna is fixed while the other one rotates with an angle ented in . A compaR = 1 λ to R = 5 λ. A comparison of the simulated results and measured results is shown in The anechoic chamber measurements were performed to verify the validity of both the computed and simulated results. The setup for the indoor measurement is shown in R = 1λ for the measurement is greater than the one of R = 0.8λ for the simulation. For the impedance matching, the simulated and measured results are similar in terms of the magnitude of the reflection coefficients, while a 3~5% shift of the center frequency between the simulated and measured results is generated. The discrepancy between the simulated and the measured one might be attributed to the use of a relatively smaller size of the tank than the human tissue model used in the simulation. The effect from the dispersive phantom fluid can be reduced due to the limited size of the tank, which results in higher resonant frequency than the full-wave simulation. The measured results provide a good agreement with the simulated results for both the power transmission and impedance matching. An excellent agreement between the simulated and measured results is observed for the different depths of the human skin. It is noted that the simulated coupling level at the shortest distance is slightly smaller than the one of This paper presents biomedical applications of the formulas to compute the mid-range wireless link in the radiative near-field region. The radiation characteristics of the implanted antennas in the radiative near-field region are studied, and the related gain reduction factor is derived. The step by step procedures from the radiation characteristics to the analysis of the wireless link are presented. The formulas require the far-field information to compute the coupling between two antennas in the radiative near-field region. An overview of the different formulations is summarized in


Alcohol consumption is an important risk factor for hepatic neoplastic and non-neoplastic diseases. Questions remain, however, about the relevance to disease risk of drinking patterns and alcohol tolerability, which differ appreciably between Chinese and Western populations.The prospective China Kadoorie Biobank included 512,715 adults (41% men) aged 30–79 years recruited from ten areas during 2004–2008, recording alcohol intake, drinking patterns, and other characteristics. After median 10 years’ follow-up, 2531 incident liver cancer, 2040 liver cirrhosis, 260 alcoholic liver disease (ALD), and 1262 non-alcoholic fatty liver disease (NAFLD) cases were recorded among 492,643 participants without prior cancer or chronic liver disease at baseline. Cox regression was used to estimate adjusted hazard ratios (HR) relating alcohol intake and drinking patterns to each disease.n = 547), 1.83 (1.60–2.09) for liver cirrhosis (n = 388), 2.01 (1.77–2.28) for ALD (n = 200), 1.71 (1.35–2.16) for NAFLD (n = 198), and 1.52 (1.40–1.64) for total liver disease (n = 1775). The association with ALD appeared stronger among men reporting flushing . After adjustment for the total amount of weekly alcohol consumption, daily drinkers had significantly increased risk of ALD  compared with non-daily drinkers, and drinking without meals was associated with significantly greater risks of liver cancer , liver cirrhosis , and ALD  compared with drinking with meals. Female current regular drinkers had significantly higher risk of ALD, but not other liver diseases, than female abstainers.Overall, 33% of men and 2% of women drank alcohol regularly (i.e. at least weekly) at baseline. Among male current regular drinkers, alcohol consumption showed positive dose-response associations with risks of several major chronic liver diseases, with HRs per 280 g/week (i.e. around four drinks/day) higher usual alcohol intake of 1.44 (95% CI 1.23–1.69) for liver cancer  may further exacerbate the disease risks.The online version contains supplementary material available at 10.1186/s12916-021-02079-1. Liver disease is a major public health problem worldwide, responsible for > 2 million deaths in 2017, including 1.3 million from liver cirrhosis and > 0.8 million from liver cancer [ALDH2 gene, which causes an accumulation of toxic acetaldehyde that leads to the alcohol flushing response after drinking) differ importantly from the West [Alcohol consumption is a major risk factor for ALD and liver cirrhosis , 5. Excethe West , 8, 9. Pthe West , 11 and the West  to affecthe West –16.To address this evidence gap, we report findings from the nationwide China Kadoorie Biobank (CKB) prospective study of 0.5 million adults. The study aims to (1) assess the associations of alcohol consumption and drinking patterns with incidence of overall and major chronic liver diseases; and (2) examine the associations of alcohol consumption with risks of liver diseases in certain population subgroups  and by the alcohol flushing response.Details of the CKB study design and methods have been previously reported . BrieflyDetailed questionnaire assessment of self-reported alcohol consumption patterns has been described previously , 18–20. Cause-specific mortality and morbidity was monitored through local death registries, cancer registries, and the national health insurance claim databases. To minimise loss to follow-up and underreporting of events, annual active follow-up through local residential, health insurance, and administrative records was conducted, supplemented where necessary by contacts with participants and/or their family members. All events were coded using the International Classification of Diseases, 10th Revision (ICD-10). The outcomes studied were incident total liver disease  and its main components, including liver cancer (C22), liver cirrhosis (K74), ALD (K70), NAFLD (K76.0), and chronic viral hepatitis . By January 1, 2017, 44,037 (8.6%) participants had died and 4781 (0.9%) were lost to follow-up.Participants with a self-reported history of cancer, liver cirrhosis, or chronic hepatitis at baseline (n=8717), or with unclear or missing HBsAg test results  were excluded, leaving 492,643 participants  in the main analyses. Given very few women drank alcohol regularly , the maiMeans and percentages of selected baseline characteristics were calculated across different drinking categories using direct standardisation to the age and study area structure of the study population where appropriate. Cox regression models were used to estimate adjusted hazard ratios (HRs) for incident liver diseases associated with alcohol drinking status (reference category: abstainers) in all participants, and with alcohol consumption level  and with drinking patterns among current regular drinkers. The analyses of the dose-response relationships with amount of alcohol intake and of drinking patterns were focused on current regular drinkers to limit potential biases from reverse causation  and residual confounding  , 22, 23.To account for within-person variation of alcohol intake over the follow-up period , repeat To investigate the potential effect modification, HRs per 280 g/week higher usual intake were examined across subgroup populations defined by HBsAg sero-status, smoking status, BMI, flushing response, prevalent diabetes (previously diagnosed or screen-detected at baseline), physical activity, and socio-demographic characteristics , with heterogeneity in effect sizes assessed by chi-squared tests .Sensitivity analyses included (1) repeated analyses with inclusion of abstainers, occasional drinkers, and ex-regular drinkers; (2) adjustments for further covariates ; (3) adjustments for other drinking habits in drinking pattern analyses; and (4) excluding participants with other prior chronic diseases  or poor self-reported health, or the first three years of follow-up.The fraction of liver diseases attributable to ever-regular drinking (including both ex- and current-regular drinking) in this study population was calculated as P(HR-1)/HR, where P was the proportion of ever-regular drinkers among those who developed the relevant liver disease in CKB . As ex-rAnalysis was done in SAS version 9.4 and R version 3.6.1.n = 66,977) reported drinking alcohol regularly in most weeks (Table n = 5896) were current regular drinkers, and they had much lower consumption (mean 113 g/week) than men  years, 41% were men, and 56% lived in rural areas, with 3% testing positive for HBsAg at baseline. Among the 201,039 men included in the main analyses, one third (0.7 yearsDuring 5 million person-years of follow-up median 10.1 years), 9139 individuals  developed liver diseases. Among men, the risks for total and most major chronic liver diseases tended to be higher among ex-regular drinkers, lower among occasional drinkers, and broadly similar among current regular drinkers , when compared with abstainers , liver cancer , liver cirrhosis , ALD , and NAFLD , but not chronic viral hepatitis   Fig. C and appThe dose-response associations among male current regular drinkers were similar with further adjustments   and non-neoplastic liver diseases , respectively, in the male study population could be attributed to ever-regular alcohol drinking , although there was a suggestion of stronger associations of alcohol intake with ALD among those who had higher BMI, or who had the alcohol flushing response. For a given level of weekly intake, drinking daily and having a longer duration of regular drinking were associated with excess risks of ALD, while drinking without meals was associated with excess risks of liver cancer, liver cirrhosis, and ALD. Among the few female current regular drinkers, the risk of ALD was significantly elevated compared with abstainers, but the associations with other disease types were less clear.A J-shaped association of alcohol consumption with chronic liver disease has been observed in previous prospective studies of Western populations , 29, witAlthough alcohol consumption has been concluded to be causally related to liver cancer by WHO-IARC , evidencAlcohol intake has been consistently shown to be associated with increased risks of liver cirrhosis and ALD in Western and high-income Asian populations –7, 30. In = 5407, 30-year follow-up) reported a twofold higher risk of fatty liver disease (defined as having a fatty liver index ≥ 60) associated with sustained heavy drinking versus stable low-risk drinking , with no reduced risks for stable low-risk drinking compared with stable non-drinking [In populations with high prevalence of obesity, fatty liver disease particularly NAFLD has emerged as a major chronic liver disease. Two meta-analyses of 18 and 16 individual studies, respectively, suggested that moderate drinking (i.e. < 20 g/day) was associated with lower risk of fatty liver disease (diagnosed and defined in various ways across different studies) compared with non-drinking , 34. Howdrinking . With a Several possible mechanisms linking alcohol consumption with different types of liver diseases have been proposed . AlcoholIt has been suggested that smoking , obesityThis is the first prospective study to report on the associations between drinking patterns and risks of many different types of chronic liver diseases in a Chinese population. The UK Million Women Study (MWS) and the Danish Diet, Cancer and Health Study have shown that daily drinking was associated with increased risks of liver cirrhosis and ALD compared with non-daily drinking (HR range 1.61–3.65), given the amount consumed . Two smaALDH2-rs671 genotype among current regular drinkers in CKB [The chief strengths of this study include the prospective study design with a large sample size, comprehensive adjustments for potential confounders, and large numbers of well-characterised liver disease events traced via comprehensive follow-up systems. The exclusions of individuals with prior diseases and early follow-up reduced reverse causality. Also, the repeat alcohol measures allowed adjustment for regression dilution bias . Our stus in CKB . Finallys in CKB , 18, we In summary, among Chinese men, alcohol consumption was positively associated with risks of major chronic liver diseases, including liver cancer, ALD, liver cirrhosis, and NAFLD. As well as total amount consumed, certain drinking patterns especially drinking without meals, drinking daily, and prolonged duration of regular drinking might be particularly harmful. While the mandatory HCV screening for blood transfusion since the early 1990s and the universal HBV immunisation programme among new-born babies since the early 2000s, respectively, are expected to have huge impacts on current and future rates of infection-related liver diseases in China , tacklinAdditional file 1.


Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents that can interfere with the process of amyloid formation or target already formed amyloid assemblies are consequently of therapeutic interest. In this context, a few endogenous proteins have been associated with an anti-amyloidogenic activity. Here, we review the properties of transthyretin, apolipoprotein E, clusterin, and BRICHOS protein domain which all effectively interfere with amyloid in vitro, as well as displaying a clinical impact in humans or animal models. Their involvement in the amyloid formation process is discussed, which may aid and inspire new strategies for therapeutic interventions. Amyloidosis refers to a variety of increasingly common human diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and diabetes mellitus type 2 (T2D). Amyloids are composed of insoluble proteinaceous material with a β-sheet rich fibrillar morphology that can reach several microns in length and are typically between 5–10 nm in diameter. They can arise from different types of proteins through a multistep process, known as amyloidogenesis. Up to date, more than 30 different proteins and peptides have been identified to form amyloid structures in vivo . The. The3]. For most of the polypeptides, amyloid formation occurs via a nucleation-dependent mechanism . HoweverAmyloid formation in vivo frequently leads to pathological changes in the affected organs, including tissue and cell degeneration and inflammation. Although the cell and tissue damages vary between different amyloid forms, the associated pathological effects are often linked to cytotoxic properties of amyloid structures. This has been observed both in vitro, on various cell lines, and in vivo on animal models ,10,11. TExperimental data on animal and cell models suggest that inhibition of amyloid formation is essential for preventing or suppressing the progression of the pathological process ,18.In the quest to prevent amyloid formation, several different strategies have been explored. Among these, a range of small molecules of both synthetic ,20,21 anA small number of endogenous proteins that display amyloid-interfering properties have potential therapeutic value, as they can serve as a more natural way of preventing amyloid formation by promoting self-regulation of protein homeostasis. Among such proteins are molecular chaperons and several proteins with diverse physiological functions, including transport. In the early nineties, it was discovered that in extracellular fluids such as cerebrospinal fluid (CSF) and serum, the highly amyloidogenic amyloid-β peptide (Aβ) forms stable complexes with some proteins and does not aggregate into amyloid ,31,32. TIn this review, we summarize the information accumulated in the literature regarding some of these proteins, which have been intensively studied in recent years, namely, TTR ,35,36,37TTR is a 55 kDa homotetrameric protein circulating in the plasma and CSF. Its main physiological function is to transport thyroid hormone thyroxine (T4) and retinol-binding protein. TTR is produced mainly in the liver  wherefrottr gene . T. T189]. Proteolytic processing of BRICHOS proteins results in the release of different peptides from C-terminal, such as Bri23 functional peptide from Bri2. Further processing can also release the BRICHOS domain to extracellular space ,192.Among the BRICHOS containing proteins, proSP and BRI families are the most studied for BRICHOS function. It is believed that the physiological role of BRICHOS is acting as a chaperone during the protein folding process, preventing them from misfolding and aggregation. ProSP-C and Bri2 contain an amyloidogenic segment and it is hypothesized that BRICHOS domain prevents these segments from forming aggregates ,194; howProSP-C, a 21kDa transmembrane protein, is expressed and secreted from the pulmonary alveolar type II cells and eventually cleaved to form a 35 residue of lipophilic mature peptide SP-C in the alveolar space to stabilize surfactants at low lung volumes ,197,198.Among the BRICHOS proteins, the Bri2 and Bri3 of the BRI family play a significant role in the prevention of neurodegenerative diseases ,202,203.An increased overall level and deposition of Bri2 in amyloid plaques of AD brains has been observed at early stages of AD development, which is accompanied by the decreased presence of Bri2-APP complexes, suggesting a loss of function of Bri2 during AD . In contStudies on transgenic Drosophila showed that co-expression of Aβ42 and BRICHOS domain in the CNS delays the aggregation of Aβ42 and significantly improves both lifespan and locomotor function compared with only Aβ42 expressing flies . MoreoveIn vitro, recombinant proSP-C BRICHOS and Bri2 BRICHOS directly interact with Aβ42, significantly reducing its aggregation already at substoichiometric levels of BRICHOS .Interestingly, different quaternary structures of BRICHOS affect qualitatively different aspects of protein misfolding and toxicity . ParticuThe mechanism by which BRICHOS inhibits Aβ amyloid formation is explored in several studies. Cohen et al., showed that BRICHOS specifically inhibits surface catalyzed secondary nucleation by binding to the surface of Aβ42 fibrils . This inRecent studies on mice showed that peripherally administered recombinant BRICHOS can pass over the BBB , and theThe inhibitory activity of BRICHOS has recently been explored also on IAPP aggregation and toxicity . The stuAmyloid-related disorders are complex pathologies involving the impairment of many biological mechanisms. Each of these diseases has unique characteristics and at the same time, they share many common and overlapping mechanisms, such as protein misfolding, aggregation and deposition, tissue degeneration, and inflammation. Moreover, the cases with the coexistence of two or more conventionally distinct pathological features are not uncommon, for example, type-2 diabetes and AD/dementia , or AD w


Introduction: To report our experience in continent urinary diversions, we describe two cases we treated performing detubularized ureterosigmoidostomy. In children, in the case of malformations or neoplastic diseases affecting the bladder, the need for a cystectomy is not so frequent. When cystectomy becomes mandatory, there is a need to create a continent bladder diversion. Mainz pouch II and Cologne pouch are procedures that utilize a detubularized sigma as a reservoir in order to build up a continent neo-bladder. Materials and methods: This is a retrospective study performed at the Pediatric Surgical Unit of the Salesi Children’s Hospital. In this work, we reviewed data about two patients who underwent surgery for the creation of a sigmoid neo-bladder by the Mainz pouch II and Cologne pouch techniques. Results: In our experience, we treated a girl who was affected by a bladder’s rabdomiosarcoma and a girl born with a bladder exstrophy and treated at birth abroad. In both patients, a complete cystectomy was performed and a continent neo-bladder was created by a detubularized ureterosigmoidostomy. In the first case, we performed the Mainz pouch II technique and in the second, the Cologne pouch technique. Discussion: Different techniques have been developed with the main goal of the creation of an orthotopic neo-bladder, which has to be a low pressure reservoir with a continent sphincteric mechanism. Detubularized ureterosigmoidostomy is a good choice in pediatric patients. Our study, according to other works, shows that these procedure are safe with good long-term outcomes. In pediatric surgery, in the case of malformations or neoplastic diseases affecting the bladder, the need for a cystectomy is less and less frequent. In cases where cystectomy becomes mandatory, there is a need to create a continent bladder diversion. Mainz pouch II and Cologne pouch are procedures that utilize a detubularized sigma as a reservoir in order to build up a continent neo-bladder. In this work, we report our experience in two patients treated with these techniques.Urinary bladder substitution is not a common procedure in children, for whom every effort is made to preserve the native bladder. However in the case of malignancies, such as rabdomiosarcoma, or malformations, such as a bladder’s exstrophy, it is not always possible to preserve the native bladder.The improvement of medical therapies and surgical procedures has reduced significantly the rate of cystectomy for bladder tumors in children. Nevertheless, in some patients, after chemotherapy and radiotherapy the bladder becomes fibrotic and functionally compromised, with no possibility to save it . MoreoveSeveral techniques allow the creation of a competent neo-bladder. Mainz pouch II and Cologne pouch are procedures that utilize a detubularized sigma as a reservoir. Several series reported good outcomes using these procedures. In this work we report our experience in two patients treated with these techniques.This is a retrospective study performed at the Pediatric Surgical Unit of the Salesi Children’s Hospital. In this work, we review data about two patients who underwent surgery for the creation of a sigmoid neo-bladder by Mainz pouch II and Cologne pouch techniques.A retrospective clinical-records review was performed on two patients operated on for the creation of a sigmoid neo-bladder by the Mainz pouch II and Cologne pouch techniques at the Pediatric Surgical Unit of the Salesi Children’s Hospital in Ancona. We collected data about the demographic characteristics, bladder pathology, diagnostic examinations, operative procedures, post-operative complications, electrolytic balance and urinary continence outcomes.In our experience, we treated a girl who was affected by a bladder’s rabdomiosarcoma and a girl born with a bladder exstrophy and treated at birth abroad. In both patients, a complete cystectomy was performed and a continent neo-bladder was created by a detubularized ureterosigmoidostomy. In the first case, we performed the Mainz pouch II technique and in the second, the Cologne pouch technique.A two-year-old girl came to our unit with abdominal pain and hematuria. A cystoscopy was performed, with evidence of a mass originating from the vesical trigone. We collected biopsies of the mass. The hystological diagnosis was a rabdomiosarcoma of the bladder. The patient started a neoadjuvant therapy and then, according to protocol, she underwent surgery. A cystectomy with the creation of a continent neo-bladder by the Mainz pouch II technique was performed A,B.The post-operative course was free from complications and the patient was discharged, entering our follow-up protocol A,B.Every two years, the patient underwent endoscopy with random biopsies to evaluate the condition of the ureterosigmoidostomy.After two years, the patient was in good condition with no complications about the pouch.During the follow-up, the patient developed a right hydroureteronephrosis due to a stenosis of the right ureterosigmoidostomy with a decrease of the right renal function. A redo ureterosigmoidostomy was performed with the complete resolution of the stenosis.To date at the last check, at 13 years of age, the patient presented in good condition, with good continence, no electrolyte imbalances, no urinary infections and blood pressure to normal values. The patient also had a MAG3 renal scan annually, which showed good renal function and no scarring.An 11-year-old girl came to our attention for a complete urinary incontinence. The patient, born abroad, presented at birth a bladder’s exstrophy that was corrected soon after with the closure of the bladder’s plate.A functional examination and a renal scintigraphy were performed, with evidence of a bilateral third degree vescicoureteral reflux with good renal function.The patient underwent a cystectomy and a Cologne pouch intervention with a complete cystectomy and creation of a continent neo-bladder with the sigma .At 12 years of age, during follow-up, the patient did not present long-term complications. Urinary continence was good, with a neo-bladder emptying nearly every 2–3 h A,B. The There were no post-operative complications and the patient was discharged in good conditions.In pediatric surgery, bladder pathologies that can lead to a severe impairment of its function and to urinary incontinence are rare. Every effort is made to save the native bladder, but in some cases a cystectomy is mandatory, with the consequent need to build up a continent neo-bladder. Different techniques have been developed, with the main goal the creation of an orthotopic neo-bladder, which has to be a low pressure reservoir with a continent sphincteric mechanism. Detubularized ureterosigmoidostomy is a good choice for the creation of a continent neo-bladder in pediatric patients. Our study, according to other works, shows that these procedure are safe with good long-term outcomes.In pediatric surgery, bladder pathologies that can lead to a severe impairment of its function and to urinary incontinence are rare but challenging. In these cases, every effort is made to save the native bladder. In some cases a cystectomy is mandatory, with the consequent need to build up a continent neo-bladder. The main indications for this kind of surgery are a bladder’s neoplasms and major malformations, such as the bladder’s exstrophy and exstrophy of cloaca. In the first case, a cystectomy is indicated when the pathology is advanced, or when, following radiation therapy, the bladder has become fibrotic, losing its continence.In the case of major malformations such as bladder’s exstrophy with polipoid changes, it is sometimes not possible to reconstruct a functioning bladder, and urinary diversion remains the only possibility.In 1852, Simon first described the diversion of urine into the rectum ,5 but prDifferent techniques have been developed over time, but the main goal of these procedures is the creation of an orthotopic neo-bladder, which has to be a low pressure reservoir with a continent sphincteric mechanism ,10.Bladder substitution in children may be performed by using either the small bowel or the colon. Both choices have as their main point the principle of detubularization. In fact, the conversion of a tubular segment of intestine into a spherical reservoir of bowel decreases the pressure and peristalsis and increases the capacity of the segment. A detubularized segment presenting a more spherical configuration results in a lower pressure reservoir with a minor absorption area, thus minimizing the appearance of ureteral reflux and metabolic complications. The other point is the importance of preventing the reflux of urine. The presence of urine reflux leads to ascending infections with serious renal injuries and a decrease in its function. The principles of tunnel or nipple valves are used for reflux prevention in uretheral intestinal implantation and are similar to those used for vesicoureteric reimplantation. Structural differences in the bowel wall may involve some procedural variations; however, the principles of the procedures are technically similar in that filling of the reservoir compresses the ureteral lumen, thus preventing the reflux of urine .These principles were applied to the ureterosigmoidostomy technique to create a rectosigmoid pouch (Mainz pouch II) in 1990 . In the Mingin et al.  describeIn addition, Rubenwolf et al.  recentlyIn a similar way, there are studies about patients treated for bladder exstrophy in which the creation of a continent urinary diversion by the Cologne pouch technique has been demonstrated to have good results. Klein et al. treated 29 patients affected by bladder exstrophy with a continence rate of 81.5%, and a low rate of complications concerning the urinary tract .The results presented in our work, although limited to a selected few cases, are comparable with those of other studies in the literature. The outcome concerning urinary continence shows that these patients are clean during the day, with an acceptable time between each bladder emptying, resulting in a good quality of life, which is essential considering the age.In our series there were no cases of metabolic imbalances, due to the fact that in our follow-up protocol, every patient was treated with carbonates administration.As a main complication, we report a right severe hydronephrosis with a decrease in renal function caused by a stenosis in the ureteric anastomosis. Unfortunately, these kinds of complications are not predictable, but they are not related to the technique itself. Conversely, we did not find any cases of urinary infections, confirming the good outcome of this procedure in terms of antirefluxive results.In this kind of surgery there is the concern of a higher risk of later malignancy, secondary to the mixture of urine and feces, which must be taken into account. In Rubenwolf et al. , 8 out oThe endoscopic examination of our patients has not found to date any pathologic changes, but a strict follow-up is mandatory in order to avoid further severe problems. Our protocol, which provides for an endoscopic examination with biopsies every two years, has proven to be effective in identifying any post-operative complications. Obviously, in the case of the aforementioned symptoms for ureteral reflux or for possible transformation of the periureteral tissue, these must lead to a prompt colonoscopic examination.In recent years, pediatric surgery has seen great development in minimally invasive surgery that also has a good application in the urological field . The lapDetubularized ureterosigmoidostomy is a good choice for the creation of a continent neo-bladder in pediatric patients. Our study, according to other works, shows that these procedure are safe with good long-term outcomes.In addition, because these techniques require no devices (bags or catheters) they are particularly suitable for patients from poor countries.Nevertheless, we include the Mainz II and Cologne pouch among the choices offered to patients requiring cystectomy and continent urinary diversion.


Elevation is involved in determining plant diversity in montane ecosystems. This study examined whether the distribution of plants in the Yatsugatake Mountains, central Japan, substantiated hypotheses associated with an elevational diversity gradient. Species richness of trees, shrubs, herbs, ferns, and bryophytes was investigated in study plots established at 200‐m elevational intervals from 1,800 to 2,800 m. The changes in plant diversity  with elevation were analyzed in relation to climatic factors and elevational diversity gradient hypotheses, that is, mass effect, mid‐domain effect, and Rapoport's elevational rule. In addition, the elevational patterns of dominance of plant functional types were also analyzed. A comparison of alpha and beta diversities revealed that different plant groups responded variably to elevation; the alpha diversity of trees and ferns decreased, that of herbs increased, whereas the alpha diversity of shrubs and bryophytes showed a U‐shaped relationship and a hump‐shaped pattern. The beta diversity of shrubs, herbs, and bryophytes increased above the subalpine–alpine ecotone. In accordance with these changes, the dominance of evergreen shrubs and graminoids increased above this ecotone, whereas that of evergreen trees and liverworts decreased. None of the plant groups showed a wide elevational range at higher elevations. These elevational patterns of plant groups were explained by climatic factors, and not by elevational diversity gradient hypotheses. Of note, the changes in the dominance of plant groups with elevation can be attributed to plant–plant interactions via competition for light and the changes in physical habitat. These interactions could alter the elevational diversity gradient shaped by climatic factors. This study examined whether the distribution of plants in the Yatsugatake Mountains, central Japan, substantiated hypotheses associated with an elevational diversity gradient. The elevational patterns of plant diversity were explained by climate and plant–plant interactions, and not by hypotheses for elevational diversity distribution. This is because the subalpine–alpine ecotone is otherwise dominated by a mixture of alpine and subalpine plants according to the mass effect. From other perspectives, the dominance of P. pumila could reduce the randomness of species distribution as postulated by the mid‐domain effect and hinder the dispersal of alpine species in lower elevations against the assumption based on the Rapoport's elevational rule. Hence, testing the elevational hypotheses in this region can contribute to the understanding of the applicability and limitations of these hypotheses.Such an examination in mountainous areas in Japan is of interest because of the characteristic vegetation at higher elevations. These areas experience strong winds and heavy snowfall owing to the influence of jet streams and winter monsoons Manabe, . The sev Okitsu, . The domIn this study, the elevational distribution of multiple plant groups in the Yatsugatake Mountains, Japan, was evaluated to determine whether the hypotheses for elevational diversity gradient  could substantiate the existing elevational patterns of the plant groups. If these hypotheses could explain the elevational patterns of plants, plant diversity can exhibit the following changes with elevation.Hypothesis 1If the elevational patterns of plants follow the mass effect hypothesis, subalpine and alpine species should coexist in the subalpine‐alpine ecotone. As a result, the alpha diversity will be the highest around this ecotone. Furthermore, beta diversity can be the highest in this ecotone owing to the coexistence of subalpine and alpine plants.Hypothesis 2If the mid‐domain effect hypothesis is applied to the elevational patterns, the overlap of species distribution will increase toward the center between the summit and base of a mountain. Consequently, the alpha diversity will be the highest around the middle elevations.Hypothesis 3If the distribution of plant species can be explained by the Rapoport's elevational rule, alpine species will exhibit larger elevational ranges than species at lower elevations. Hence, the alpha diversity will be relatively high at lower elevations where both alpine and lowland species coexist.Hypothesis 4If the three elevational hypotheses do not apply to the observed patterns of plant distribution, other factors, such as climate and plant–plant interactions, will largely determine their distribution. Specifically, the influence of plant–plant interactions may be presented in relationships between the ecological traits of plant groups .22.1Quercus crispula and Larix kaempferi below ~1,800 m; subalpine conifer forest dominated by Tsuga diversifolia, Abies veitchii, and Abies mariesii f. hayachinensis at ~1,800–2,600 m; alpine dwarf pine scrub dominated by P. pumila at ~2,600–2,800 m; and alpine meadow with turf‐rock vegetation at ~2,800–2,900 m. The highest and lowest mean temperatures in the nearest weather station at 1,350 m are 19.2°C in August and −5.3°C in January, and the mean precipitation is 1,439.9 mm/year  along two trails, extending from the east to the west of the Yatsugatake Mountains Figure . This plann), mean temperature during the growing season (Tempgrow), mean temperature during the snow season (Tempsnow), mean annual RH (RHann), mean RH during the growing season (RHgrow), mean RH during the snow season (RHsnow), and duration of the snow season (snow cover). A series of snow‐covered days with over 90% RH was defined as the snow season. This definition was based on a primary experiment in which data loggers were buried under a snow pack. The remaining days were defined as the growing season. RHsnow was not used in the following analysis because this variable is nearly uniform according to its definition.To examine the influence of climate on plant diversity, temperature and relative humidity (RH) were measured in each plot at ~5 cm above the ground at 4 hr intervals throughout the year, using HOBO U23 Pro v2 temperature/relative humidity data loggers (Onset Computer Corporation). To reduce the influence of sunlight on the measurements, the data loggers were covered with a CO‐RS1 solar radiation shield (Onset Computer Corporation). Using the temperature and RH data, the following climatic variables were calculated: the mean annual temperature  with log‐link function and Poisson distribution. Models were selected as follows (model selection 1). Both linear and second‐order polynomial models were constructed, and the final model with significant coefficients and the lowest second‐order Akaike information criterion (AICc) value was selected. If a model did not have significant coefficients, then the model with the lowest AICc value was adopted.r > 0.5) were selected as explanatory variables. The models with different combinations of these explanatory variables were then constructed. Among these models, the final model had significant coefficients and the lowest AICc value.The influence of climatic factors on alpha diversity was also analyzed using GLMs with log‐link function and Poisson distribution. The final model was selected as follows (model selection 2). Climatic factors that strongly correlated with alpha diversity . The final model was selected according to model selection 1. The influences of climatic factors on beta diversity were analyzed using LMs. The final model was determined based on model selection 2.Beta diversity was evaluated using the The elevational patterns of plants were further discussed in relation to the changes in plant functional types. Plant functional types are groups of species that respond similarly to environmental and biotic changes   collected in central Japan , plant diversity databases  of trees, shrubs, herbs, ferns, and bryophytes was 5.00 ± 1.81, 2.50 ± 2.32, 9.42 ± 5.14, 2.00 ± 1.86, and 41.00 ± 17.00, respectively  were recorded in the study plots. The species richness per plot  but negatively correlated with Tempann  and Tempgrow . In contrast, no significant correlations were observed between elevation and the RH variables (RHann and RHgrow). These variables were the highest at the mid‐elevations, showing hump‐shaped relationships with elevation.The changes in climatic factors with elevations are presented in Appendix 3.2The alpha diversity of the plant groups varied with elevational distribution Figure . All coeann and Tempsnow presented significant positive effects on the alpha diversity of trees and ferns. The alpha diversity of shrubs negatively correlated with the RHgrow, whereas that of herbs positively correlated with snow cover and that of bryophytes positively correlated with Tempann and RHgrow.The results of alpha diversity and climatic factors obtained using GLMs are shown in Table 3.3Species richness  was predicted using a discrete mid‐domain effect model to examine the applicability of this hypothesis to the sampling site Figure . In all 3.4sim index) was plotted against elevation  have started to dominate the subalpine–alpine ecotone instead of evergreen conifer trees . These groups and indices are necessary to understand the characteristics of plants’ responses to elevation and their interactions that influence elevational diversity distribution.The author declares no conflicts of interest.Yoshitaka Oishi: Conceptualization (lead); data curation (lead); formal analysis (lead); funding acquisition (lead); investigation (lead); methodology (lead); project administration (lead); supervision (lead); validation (lead); visualization (lead); writing – original draft (lead); writing – review and editing (lead).Appendix S1‐S7Click here for additional data file.


Attempts to manage the COVID-19 pandemic have led to radical reorganisations of health care systems worldwide. General practitioners (GPs) provide the vast majority of patient care, and knowledge of their experiences with providing care for regular health issues during a pandemic is scarce. Hence, in a Danish context we explored how GPs experienced reorganising their work in an attempt to uphold sufficient patient care while contributing to minimizing the spread of COVID-19. Further, in relation to this, we examined what guided GPs’ choices between telephone, video and face-to-face consultations.This study consisted of qualitative interviews with 13 GPs. They were interviewed twice, approximately three months apart in the initial phase of the pandemic, and they took daily notes for 20 days. All interviews were audio recorded, transcribed, and inductively analysed.The GPs re-organised their clinical work profoundly. Most consultations were converted to video or telephone, postponed or cancelled. The use of video first rose, but soon declined, once again replaced by an increased use of face-to-face consultations. When choosing between consultation forms, the GPs took into account the need to minimise the risk of COVID-19, the central guidelines, and their own preference for face-to-face consultations. There were variations over time and between the GPs regarding which health issues were dealt with by using video and/or the telephone. For some health issues, the GPs generally deemed it acceptable to use video or telephone, postpone or cancel appointments for a short term, and in a crisis situation. They experienced relational and technical limitations with video consultation, while diagnostic uncertainty was not regarded as a prominent issueThis study demonstrates how the GPs experienced telephone and video consultations as being useful in a pandemic situation when face-to-face consultations had to be severely restricted. The GPs did, however, identify several limitations similar to those known in non-pandemic times. The weighing of pros and cons and their willingness to use these alternatives shifted and generally diminished when face-to-face consultations were once again deemed viable. In case of future pandemics, such alternatives seem valuable, at least for a short term. On March 11th, there were 514 confirmed cases and the government announced a lockdown of society to alleviate the spread . And in that case, I think it is difficult. So, I do not really think that video is good for sensitive conversations.” As some interviewees stated, they usually get an impression of a patient already when they pick them up in the waiting room, or when they enter the consultation room. The GPs found that some of the connection, presence and intimacy suffer when there is a screen between them and their patient. This is due to three main reasons: 1) interruptions from technical problems and other people being present in people’s homes during the consultation; 2) the GP and the patient do not have eye contact because one cannot simultaneously look at the camera and at the other person on the screen; and 3) the GP cannot lay a comforting hand on the patient in times of distress. For these reasons, several GPs found these consultations less appropriate in the case of existential crises and sensitive conversations.“But we also have a safety net under us in that we always say that if we, during the conversation, assess that it cannot be done this way, then the patient quickly gets an appointment for an assessment up here instead.” In relation to clinical assessments, the GPs described how limiting it can be not to be able to see and physically examine their patients nor take spontaneous tests during the consultation. However, increased diagnostic uncertainty was not a prominent issue. The GPs generally expressed that they felt they had a safety net because they could reschedule a consultation for a face-to-face follow-up in case of doubt."Video, it's actually almost gone again, and it's kind of surprising, but, uh, but it was not that easy to implement, and my impression was that more than half of the video consultations actually had to be followed up by face-to-face consultations because you could not clarify the problem on video” During the second interview, a couple of GPs described having experienced that their patients either returned more often after video consultations, or that they had to reschedule a large proportion of the video consultations into face-to-face consultations due to the insufficiency of the video consultation.As a consequence of such experiences, some GPs chose to expand their use of face-to-face consultations again. They found face-to-face consultations more thorough, enabling the health issue at hand to be dealt with fully within only one consultation.The GPs experienced that knowing the patient well was crucial when they had to change the usual consultations to video and telephone. When they knew their patients well, which they usually did, they also knew how each patient typically presented, and they felt able to see and hear whether everything looked and sounded as usual. They also found it easier to assess the level of urgency because they knew whether the patient usually contacted them with minimal issues or had a tendency to exaggerate the situation, or the opposite. They also knew which patients were capable of waiting and observing a potential worsening of a condition, and who were not. Hence, they felt that knowing the patient could compensate for some of the disadvantages of video and telephone consultations. In support of this understanding, one GP had experienced that video and telephone consultations were more difficult for GPs in training who did not know the patients. A few GPs even believed that when they knew the patient, telephone consultations worked just as well as video consultations for some issues. Lastly, in case of minor and delimited health issues, the GPs found this familiarity as being less crucial.“Everyone with respiratory symptoms, whether they are there because they are chronic ill patients, or they turn up because of the respiratory symptoms, they do not come up here, and we do not come out to them. There, we handle it on telephone. It also means that there are some for whom we under other circumstances would do a lot to avoid giving antibiotics, but to whom we right now by telephone end up having to say: ‘well we will have to try some penicillin’.” When not seeing the patients physically, and thereby not having the optimal basis for accurate clinical decision making, many of the GPs mentioned that their prescription of pharmaceuticals was a bit more liberal. Here, they generally mentioned antibiotics prescribed for COPD exacerbations, otitis media, sore throat, pneumonia symptoms, and sinusitis.Similarly, because they could not perform a spirometry, patients suspected of having asthma were given medicine using a more trial and error approach. Further, unlike the usual practice, some GPs renewed prescriptions without having first seen the patient in the clinic, and some mentioned prescribing tranquilizers, morphine or other pain relievers on the basis of a telephone consultation, as well. However, under the given circumstances, this prescribing behaviour was considered better than first having a face-to-face consultation, which might increase the risk of spreading COVID-19.patients’ abilities and opportunities and the technical quality and disturbances. The GPs experienced that some patients did not have the needed technical competencies or equipment. Some also had difficulties sitting correctly in front of the camera or handling it when they had to show things on their body. Here, the GPs also mentioned the work involved in informing patients about the technical issues before a video consultation. Further, the technical solution for video consultations was ill-suited for nursing homes. Some nursing homes lacked portable equipment that enabled them to bring the video consultation to the patient, and if the staff had to confer with the GP about several patients at the same time, the log-in to the video consultation was problematic because it could only be linked to an individual patient and not to the nursing home as a unit. Concerning the technical quality and disturbances, the GPs often experienced the quality of the pictures as being insufficient for diagnostic purposes due to the pixilation and limited sharpness of the pictures. Hence, some GPs asked their patients to send photographs instead. They also experienced technical disturbances in the form of poor internet connections and delayed or disappearing sound and picture during the consultations.“The quality of the video camera and the sharpness of the image, if you want to observe, for example a rash or swelling, it requires the patient being able to get the camera angled in the right place and that the light and the distance to what we want to see is okay […]. It is also preferable to use a Wi-Fi connection. A 3G network pixelates it and makes it blurry. It also means that some contrasts and sharpness are lost, and then you cannot really use it.” The technical limitations involved both the A GP described that even though he felt psychologically closer to the patient when using video compared to the telephone, the technical disturbances could influence the focus of their conversation and therefore make it less preferable. On the other hand, another GP found that some of the initial challenges had been overcome, and the videos were well-functioning when used."Video consultations are perhaps primarily for these other things, such as annual checks-ups, checks-ups for other things, where you have test results to consider, and some of it you can take over the phone, but personally I like to be able to see the person.” There were different reasons behind the GPs’ choosing between video and telephone consultations. Some mainly chose video consultations and only used telephone consultations when their patients were not able to use video, or because they had to switch a planned video consultation to the telephone due to technical problems. These GPs found it valuable to see the patients while talking to them, no matter the content of the consultation.“We only choose video when it will give us something extra, that is, where there is something we need to look at on the patient, a rash or movement, they need to point to the place where it hurts or a conversation about depression where you have to see what their face looks like and their facial expressions and that sort of thing. But otherwise, a lot is done on the phone, for sure.” Other GPs only chose video if they needed to see the patient for clinical reasons, for example, to examine a rash, or to conduct conversational therapy where being able to observe facial expressions is important.These GPs perceived the telephone consultations to be as good as or preferred over the video consultations because it was easier when they only had to talk about data (e.g. test results), or because they did not believe it to be possible to diagnose the patients over video anyway. Here, some preferred a combination of telephone consultations and the patient sending in a photograph. With the possibility of having extended telephone consultations reimbursed, some stated that they actually realised how much can be done in this way. Hence, some GPs described that although they had anticipated they would use video consultations, they had increased their use of telephone consultations over video consultations.In the initial phase of the pandemic, the GPs re-organised their usual clinical work profoundly. Most consultations were held over video or telephone, postponed or cancelled. Initially, the use of video and telephone consultations rose, but soon declined when the GPs deemed that face-to-face consultations were once again permissible. This decision was made both in relation to the infection pressure and the need to reopen society. When re-organising their practice, GPs considered how to minimize the risk of COVID and COVID complications, and they followed central guidelines and their own preference for face-to-face consultations. There were variations both over time and among the GPs regarding for which health issues video and telephone were used. Video, and in some cases the telephone, were found useful while there were restrictions on the use of face-to-face consultations, and these were generally found to be more suitable for simple and delimited issues. The GPs experienced some relational and technical limitations, whereas diagnostic uncertainty was not a prominent issue.Data from the Danish general practitioners’ organisation on the national use of video and telephone consultations correspond to our findings . The useThis study aligns with and expands the existing knowledge on alternative consultation forms. In previous studies on video consultations, similar challenges concerning the relational and technical issues were identified –12. HoweIn a recent study of video consultations during COVID in Spain, the GPs perceived such consultations as an adequate option, providing the benefit of reduced infection risk while having both verbal and non-verbal possibilities in comparison with telephone consultations. The potentially negative issues identified were again the technical, physical and relational limitations . However“the crisis has provided a golden opportunity for large scale usage to be researched and for the findings of earlier research to be revisited”. They question whether their experiences with video consultations during the pandemic might change the GPs’ reluctance towards video and its perceived limited usefulness, or whether clinicians will revert to their usual practice at the first opportunity [In their discussion paper, Bidmead and Marshall  considerortunity . In theiortunity . Within ortunity . Our stuOur study suggests that the GPs’ weighing of the benefits and limitations of alternative consultation forms is context-bound and therefore varies with changing conditions, options and challenges, which again influence their willingness to use these alternatives. Whereas limitations seem less dependent on the context , the weighing up of these limitations with the potential benefits and need for alternative consultations might differ. The context influencing both their weighing-up of the limitations and willingness to use alternative consultations in this study can be attributed to four contributing factors: the changing infection pressure and the associated assessment of the viability of face-to-face consultations; the safety net option (the possibility of converting to a face-to-face consultation); the belief that the pandemic would have a limited time span; and the challenges when conducting video consultations. Their choice of whether to use video or telephone was also influenced by situational circumstances. Although some found new possibilities by using extended telephone consultations, it seemed that the telephone was primarily a viable alternative to video either because of technical challenges with the video consultations or because the GPs already saw most of their patients face-to-face. Diagnostic uncertainty was not a prominent issue in this study. A study from the early phase of the pandemic found that Flemish GPs’ who used telephone consultations as their primary source of contact feared missing a diagnosis because they had to rely on their patients’ descriptions and self-examinations . Once agIn other settings and in non-pandemic times, other contextual circumstances, such as geographical distances, technical limitations, the types of patients etc., might influence the weighing up of the benefits and limitations and hence willingness to use these alternatives. Moreover, as we demonstrated, willingness is also influenced by individual GP preferences and presumably also patient preferences (which we have not explored). Hence, our study shows the importance of incorporating contextual conditions and preferences when considering and planning for alternative consultation forms.This study provides insights into the reorganization of consultations in the first months of the pandemic. It is a strength that we interviewed the GPs twice, which ensured deeper insights into both the initial and changing practices and experiences as the pandemic developed. However, due to the continuously changing pandemic and a re-rise in infection rates after our data collection, a third round of interviews could have been additionally enlightening. Eleven of the GPs provided daily notes for our research project, and these notes gave us a good impression supplementary to the interviews of how daily work in the clinic was affected by the pandemic; for example, how the GPs experienced the development in the guidelines, testing capacity, and the use of video consultations. Further, our study broadens the knowledge on the use of alternative consultation forms as it depicts a real life setting and an unselected group of GPs who have not initiated their use due to a special interest or participation in a research study.In the initial months of the pandemic, GPs re-organized their clinical work. They first converted a vast number of consultations to video or telephone, or postponed or cancelled them, and later on increasingly resumed their usual practice. They were guided by their intention to minimise the risk of COVID, the national guidelines, and their own preference for face-to-face consultations. Video, and in some cases the telephone, were found to be useful when there were restrictions on the use of face-to-face consultations. The GPs experienced the same kinds of limitations and drawbacks as have been previously found in non-pandemic times, which influenced their willingness to use these alternatives. The weighing of pros and cons and their willingness to use these options shifted and generally diminished as soon as face-to-face consultations were deemed viable. This reduced buy-in is worth taking into account in non-pandemic times if considering a more general roll-out and implementation of video or telephone consultations in general practice. However, in future pandemics or other situations with a need for radical changes of medical work, these alternatives seem valuable, at least for a limited period of time, when seeking to uphold adequate patient care in general practice.


Background: Binge drinking and smoking among adolescents are serious public concerns. However, very few studies have explored the reinforcement of bullying victimization by such behavior. Our study aimed at examining the individual and combined associations of smoking and bullying victimization with binge drinking among adolescents in Beijing, China.Methods: A total of 33,694 students aged 13–17 years old in Beijing, China were anonymously investigated via the cross-sectional Chinese Youth Risk Behavior Surveillance Survey from April to May 2014. A three-stage stratified sampling was used to select participants. Factors such as sociodemographic variables and indicators of smoking, bullying victimization, and binge drinking were analyzed with multiple logistic regressions, and joint and additive interaction effects were tested.Results: Overall, ever-drinking prevalence was 59.1% . Past 30-day binge drinking was 11.5%  and frequent binge drinking was 2.3% . Past 30-day smoking was 10.7%  and past 30-day bullying victimization was 48.7% . The combined effects of smoking and bullying victimization on occasional binge drinking  and frequent binge drinking  were significant, and the additive interaction effect was significant for current smoking and bullying victimization on frequent binge drinking . The additive interaction effect for current smoking and bullying victimization on frequent binge drinking was significant among boys.Conclusion: Bullying victimization reinforced the association of smoking with frequent binge drinking, especially with findings specific to boys. Programs to prevent smoking or bullying or both may reduce binge drinking among adolescents in China. The use of alcohol significantly affects adolescents' physical and mental health around the world  and contPrevious research has identified that tobacco consumption and alcohol abuse are highly correlated with each other during adolescence , specifiWe hypothesized that smoking and bullying victimization might influence binge drinking, whereby the effects would be additive. The combined effect of smoking and bullying victimization on binge drinking was larger than the sum of the individual effects. Bullying victimization might reinforce the association of smoking with binge drinking. The Chinese Youth Risk Behavior Survey (CYRBS) conducted in Beijing provided us an opportunity to assess the effects. In this large representative sample of Chinese adolescents, we examined overall binge drinking and frequent binge drinking—defined as binge drinking for more than 5 days in the past 30 days—and aimed to assess the strength of smoking and bullying victimization on binge drinking alone and as combined effects in interaction. Given the known differences in the prevalence of alcohol use according to gender, we separately tested the overall effects for boys and girls.A cross-sectional survey was conducted among 33,694 middle and high school students (aged 13–17) in Beijing, China, from April to May 2014. The sampling procedure, as previously described in , 23, wasAfter reviewing previous studies on binge drinking, we identified and adjusted for the following binge drinking-related factors in our study . SociodeThe feeling of loneliness was measured by “How often you feel lonely in the past 12 months,” and the answer options included “never,” “rarely or sometimes,” and “often or always.” The fighting experience was assessed by “How many times have you fought with others in the past 12 months,” and the answer options included none, 1–3 times, 4–5 times, and >5 times.Alcohol use was determined by a report of having consumed at least one drink of alcohol in one's lifetime. Never drinkers were defined as participants who never consumed alcohol. Participants who consumed alcohol were considered as ever drinkers if they reported not drinking alcohol during the past 30 days. Binge drinking was defined as drinking at least five glasses of alcohol within 1–2 h. Among ever drinkers, past 30-day binge drinking was classified as “none (0 days)” and “binge drinking (1–30 days)”; we also divided “binge drinking (1–30 days)” into “occasional binge drinking (1–5 days)” and “frequent binge drinking (6–30 days)” . AdditioThe smoking status was assessed by asking the question: “Have you ever tried cigarette smoking, even one or two puffs?” Participants who answered “No” were defined as never smokers and participants who answered “Yes” but not smoking in the past 30 days were coded as former smokers. Current smoking was defined as smoking a cigarette in the past 30 days .Bullying victimization was measured by asking, During the past 30 days, (A) have you been maliciously teased? (B) have you been made fun of using gender-related jokes, comments, or gestures? (C) has anyone made fun of your individual physical imperfections or appearance? (D) have you been deliberately excluded from a group activity? (E) have you been threatened or intimidated? (F) have you been blackmailed for money? or (G) have you been hit, kicked, pushed, squeezed, or locked indoors? Different types of victimization experiences were presented as separate items. A report of “Yes” on any of the victimization experiences was categorized as positive for bullying victimization. First, we examined different types of victimization experiences and then a composite of any bullying experience.p < 0.05. All data were analyzed using SPSS 22.0 for Windows .Frequencies were calculated to summarize the distributions of the categorical variables. Chi-square tests were performed to examine the distributions of the categorical behavioral variables with gender and school level (middle vs. high school). The binary logistic model (model 1) was developed using sociodemographic factors, smoking status , and different types of victimization experiences as independent variables and drinking status (drinkers/non-drinkers) as the dependent variable. Among drinkers, multinomial logistic models were established to explore the joint effect of smoking and bullying victimization on binge drinking (model 2 and model 3). To explore this interaction effect of smoking and bullying victimization on binge drinking, logistic models were established with bullying victimization × smoking as the interaction item. To explore the difference between the interaction effects of binge drinking on boys and girls, a gender stratification analysis was conducted. The presence and direction of interaction depend on the scale, e.g., additive or multiplicative. Additive interaction means that the combined effect of two exposures is larger  than the sum of the individual effects, and multiplicative interaction means that the combined effect is larger  than the product of the individual effects of the two exposures . All modThis sample of 33,694 students was largely balanced for gender  and school level ; 32.5% reported their mothers' highest education was middle school and below; 24.2% were boarding students, and 73.2% reported average academic achievement. Overall, 19.8% reported a record of fighting , 7.6% watched television 4+ h per day, and 15.4% played video games 4+ h per day .Overall, 59.1% reported ever drinking alcohol, higher among boys (64.4%) than girls (53.7%) and among high school students (67.5%) than middle school students (48.5%). For the full sample, past 30-day alcohol use was reported by 31.5% of students, higher among boys (37.2%) than girls (25.8%) and among high school students (36.8%) than middle school students (24.8%). Among ever drinkers, past 30-day alcohol use was reported by 51.6% of students (55.7% of boys and 46.6% of girls). For the full sample, past 30-day binge drinking was reported by 11.5% of students, higher among boys (15.6%) than girls (7.4%) and among high school students (14.8%) than middle school students (7.3%). Among ever drinkers, past 30-day binge drinking was reported by 18.7% of students (23.2% of boys and 13.4% of girls). Among ever drinkers, symptoms of drunkenness were reported by 20.3% of students .Overall, 24.3% reported former smoking (31.8% of boys and 16.8% of girls), and 10.7% reported past 30-day smoking (16.4% of boys and 5.0% of girls). More high school students (31.2%) than middle school students (15.5%) reported former smoking and more high school students (14.9%) than middle school students (5.4%) reported current smoking.By frequency, the top four bullying victimization behaviors were being maliciously teased (35.9%); being made fun of by gender-related jokes, comments, or gestures (21.7%); being made fun of individual physical appearance (15.5%), and being deliberately excluded from a group activity (13.1%). Across all categories of bullying, except for being made fun of physical defect or appearance, boys were more likely to be bullied than girls .Compared with never smokers, former smokers  and current smokers  were more likely to report ever drinking. The bullying victimization behaviors of being (A) maliciously teased ; (B) made fun of gender jokes, comments, or gestures ; and (C) made fun of individual physical imperfections or appearance  were associated with ever drinking; while (D) being deliberately excluded from a group activity  and (G) being hit, kicked, pushed, squeezed or locked in a room  were associated with less likelihood of ever drinking. The bullying victimization behaviors of being (E) threatened or intimidated and (F) blackmailed for money were not significantly associated with ever drinking . In addiThe remaining analysis was restricted to ever drinkers. Compared with never smokers who were not bullied, students who were former smokers and victims of bullying , and students who were current smokers and victims of bullying  were prone to a greater risk of binge drinking. The findings were identical to those of occasional binge drinking . The addSome sociodemographic variables were significantly associated with binge drinking (1–30 days) among ever drinkers .Students who were found to be binge drinking had a history of smoking and experience of bullying in their lives . MoreoveWhen stratified according to gender, the findings were generally similar –12; howeIn this large scale adolescent age sample, the ever-drinking prevalence was 59.1%, which was consistent with other reports on adolescents' ever drinking prevalence in China, which ranged from 50 to 67% , 4, 31. In the global status report on alcohol and health 2018, the WHO suggested that the Western Pacific Region should raise awareness and advocacy of alcohol-related harm . The actIn the present study, former and current smoking were associated with binge drinking, which was consistent with previous studies , 14. We Our findings identified that bullying victimization reinforced the association of smoking with frequent binge drinking among boy drinkers, which indicates that increased attention should be paid to boys to prevent adolescent bullying and smoking and the efforts might be more beneficial for boys than girls. However, concerning the effects of interaction between smoking and the experience of any bullying victimization on occasional binge drinking, we did not find significant interaction effects of smoking and the experience of any bullying victimization on occasional binge drinking, which meant that the former smoking and experience of any bullying victimization individually influenced the occasional binge drinking instead of as a combined effect. To our knowledge, this study is the first to report on the interaction between smoking and bullying victimization on frequent binge drinking in China. The additive interactive effect on frequent binge drinking was significantly higher than the sum of the individual effects. The findings support efforts by governmental health and education agencies, local schools, and parents to prevent adolescent smoking and bullying, which might help prevent binge drinking. An example of such efforts was China's Ministry of Education's special governance on school bullying prevention that was released in 2016, to reduce the occurrence of school bullying .For the intervention on binge drinking, the problem behavior theory might be an effective theory , which hA positive association was found with ever drinking  in three of the seven bullying victimization experiences that we examined; whereas, two of the bullying victimization behaviors  were associated with a lower likelihood of ever drinking. The three bullying victimization experiences that were positively related were all verbal bullying. Physical bullying was directly reflected in physical injuries, and teachers and parents tended to conduct, in a timely fashion, psychological counseling for bullied students. However, verbal bullying was reflected psychologically, not physically, and was easily ignored by parents and teachers. Therefore, parents and teachers should not only focus on physical bullying, but also pay attention to students who are verbally bullied, and teach students how to properly protect themselves when they are bullied.The present study covered a relatively large sample size and identified the effects of additive interaction between current smoking and bullying victimization on frequent binge drinking in adolescents in China. This study found the interaction between smoking, binge drinking, and bullying among Chinese adolescents, thereby providing theoretical support for the understanding of bullying and binge drinking among adolescents. It also provided theoretical support for bullying and binge drinking interventions in various regions. Limitations of this study included the cross-sectional design and the fact that all data were self-reported by students, which might be susceptible to recall and social desirability biases. Considering the self-reported variables, adolescents tend to underreport substance use and bullying victimization. Given the study's cross-sectional design, causation cannot be inferred from the associations identified. While bullying victimization and smoking might cause binge drinking, binge drinking might lead to current smoking and bullying victimization, or a third variable might drive the observed associations. For example, in adolescence, bullying victimization , alcoholThe prevalence of drinking and binge drinking among adolescents was 59.1 and 11.5%, respectively, in Beijing, China. It was higher among boys and high school students. Smoking and bullying victimization were significantly associated with binge drinking. Adjusting for sociodemographic factors, the significant additive interactive effects of smoking and bullying victimization on frequent binge drinking were observed, and they indicated that bullying victimization reinforces the effect of smoking on frequent binge drinking among boys who drink. Preventing smoking and bullying may help prevent binge drinking.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Peking University's Medical Research Ethics Committee approved the study protocol (IRB00001052-17010). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.LC and YS conceived and designed the study. LC carried out the initial analyses and prepared the first draft of the manuscript. YS, JP, JM, PL, and GZ critically reviewed and revised the manuscript. YS, J-LD, and R-RL conducted the research and collected the data. All authors read and approved the final manuscript.The present study was supported by the National Natural Science Foundation (Grant No. 81673192 to JM) and Humanities and Social Sciences Planning Fund Project, Ministry of Education, People's Republic of China (19YJA890022 to YS).JP has provided consultation to pharmaceutical and technology companies that make medications and other treatments for quitting smoking and has served as an expert witness in lawsuits against the tobacco companies. The remaining 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.