Third, formulae and ratios are provided for heuristic modelling of effects on external action (eS). Fourth, examples are provided of heuristic modelling of disturbances in psychomotor work. Fifth, formulae and examples show how task complexity can be modelled heuristically in terms of microstates across the cyber domain and the physical domain of cyber-physical systems. Overall, the study reported in this paper addresses variational aspects of PLPA.Optimal psychomotor work can be expressed in terms of the principle of least psychomotor action (PLPA). Modelling psychomotor action encompasses modelling workers, work, and interactions between them that involve different types of situated entropy. Modelling of psychomotor workers encompasses three types of workers: human, cyborg, and robot. The type of worker and the type of work interact to affect positioning actions, performing actions, and perfecting actions undertaken in psychomotor tasks. There are often disturbances in psychomotor work, for example due to weather conditions, which have a determining influence on what work can be undertaken with least psychomotor action by different types of workers. In this paper, findings are reported from a study focused on the modelling disturbances in psychomotor work. Five contributions are provided. First, a heuristic framework for modelling disturbances and their effects is provided. In addition to PLPA and situated entropy, this framework encompasses Markov processes, the theory of perturbations, and calculus of variations. Second, formulae and ratios are provided for heuristic modelling of effects on internal action ( Third, formulae and ratios are provided for heuristic modelling effects on external action (eS). Fourth, examples are provided of heuristic modelling of disturbances in psychomotor work. Fifth, examples show how task complexity can be modelled heuristically in terms of microstates across the cyber domain and the physical domain of cyber-physical systems. Together, these contributions enable heuristic modelling of effects from disturbances on interactions between diverse psychomotor work and workers: rather than on autonomous systems 13.36 + 0.5(29.85 − 13.36)13.36 + 8.24521.612^(3.74) + 0.5[2^(4.90) × 1.1 − 2^(3.74)]13.36 + 0.5[(29.85 × 1.1) − 13.36] 13.36 + 0.5[32.84 − 13.36]13.36 + 0.5[19.47]13.36 + 9.73823.102^(3.74) + 0.5[2^(4.90) × 1.5 − 2^(3.74)]13.36 + 0.5[(29.85 × 1.5) − 13.36] 13.36 + 0.5[44.78 − 13.36]13.36 + 0.5[31.41]13.36 + 15.7129.07eS is lowest for the human worker and highest for the robot worker due to their respective motion ratios (1/1.5).In this example, where work complexity is the same for all types of workers, However, it cannot be assumed that work complexity will always be the same for all worker types. Rather, work settings, work composition, and work uncertainty need to be engineered to minimize the effects from disturbances for different types of workers.int and SeS. As shown in intS and eS are not required. For example, a human worker’s re-positioning actions can involve automaticity in the highly flexible deployment of general psychomotor abilities. Re-positioning actions can involve known solutions, comprising gross and fine general psychomotor abilities, which enable the human worker to move forward fluidly to get into position. For a cyborg worker, such as a human wearing a motorized exoskeleton, increased strength and endurance from wearable mechatronics can be offset by reduced biomechanical flexibility. For example, the exoskeleton framework can restrict medial and lateral rotation . This caFor workers, performing actions involve applying known solutions comprising different levels of psychomotor work skills schema. The higher the level of known solution that can be applied, the lower can be the number of iterations required following disturbance because the final deviation from optimal solution. However, some types of psychomotor work inevitably require application of low level work skills schema.For example, clothing production involves shaping materials through cutting and forming parts through sewing. This is because the production of soft products such as clothing is not suited to parts consolidation techniques, which involve integration of many loose small parts into a few large assemblies . SimilariS for this example where 0.54 and 1.00 are clearly lower than 1.37 and 2.75. However, the 1/1.5 motion ratio for human worker to robot worker necessitates calculation of As shown in 2^(1.37) + 0.5[2^(2.75) − 2^(1.37)]2.58 + 0.5(6.73 − 2.58)2.58 + 2.074.652^(0.54) + 0.5[2^(1.00) × 1.5 − 2^(0.54)]1.45 + 0.5[(2 × 1.5) − 1.45] 1.45 + 0.5[3 − 1.45]1.45 + 0.5[1.55]1.45 + 0.722.17eS despite the 1/1.5 motion ratio of human worker to robot worker. Cyborg workers are not considered in this example because cyborg technologies, such as powered gloves, are not suited to the fine psychomotor skills involved in resewing.This example illustrates that robot workers can have lower With regard to perfecting actions, psychomotor work skills can be considered across a continuum from closed to open. An example of a closed psychomotor work skills is typing in office work, which involves development of routine expertise in one manual skill with one tool and one type of material. An example of an open skill is any of the craft skills in construction work that involve developing adaptive expertise encompassing many different skills with many different tools and many different types of materials. In between the most closed and most open work skills are those skills acquired in factory work through job enlargement, for example in order to undertake several different tasks in car assembly work . For worS from disturbances should be informed from the outset by understanding of the limitations of different types of workers in relation to different types of work. Moreover, these examples highlight that the fundamental question in determining how work can be carried out with least action is how can work be engineered to reduce the number of different ways in which different worker types can undertake positioning and repositioning, performing and reperforming, and perfecting and reperfecting? In simple terms, there are no skill shortages where there is zero situated entropy because there is only one way that work can be carried out and there is no uncertainty about what that one way is to the type of worker undertaking the work. However, the question about how to engineer for zero situated entropy needs to take into account the effects of disturbances, rather than engineer only for the flow state and ignore the occurrence of disturbances, because individual disturbances have low frequency of occurrence and low temporal predictability.As these examples illustrate, modelling of effects on intS) from disturbances to psychomotor work. Third, formulae and ratios are provided for heuristic modelling of effects on external action (eS). Fourth, examples are provided of modelling disturbances heuristically in psychomotor work. Fifth, formulae and examples show how task complexity can be modelled heuristically in terms of microstates across the cyber domain and the physical domain of cyber-physical systems. Overall, the study reported in this paper addresses variational aspects of PLPA. This is important because psychomotor work is beset by disturbances, and decisions about how best to deploy what types of workers needs to be informed by analyses of disturbed tasks, as well as the optimal undisturbed tasks. Production disturbances have been modelled previously in manufacturing [Building upon previous studies ,6, this acturing ,2 and inacturing ,4. Howevacturing ,2,3,4, rThe contribution of the three papers together ,6 is to John von Neumann opined that mathematical models should describe phenomena from a reasonably wide area and should be simple . Such maWe have used a two-state Markov model to capture the dynamic behavior of different types of workers. An essential part of the model is the so-called stationary distribution of the flow and choke states. As we pointed out in the


Lutraria rhynchaena Jonas, 1844 is of great commercial interest, but its reserves have dramatically declined over recent decades. Therefore, there is an urgent need of scientific basis to propose effective fishery management measures and improve artificial aquaculture of the clam. In this study, we investigated the distribution and density of L. rhynchaena, sediment characteristics, and established the clam’s reproductive cycle through monthly observations from August 2017 to July 2018. The study results showed that distribution and density of clams are related to sediment types, and the sediment type of medium sand is likely the best benthic substrate for the clams. The spawning of clams occurred throughout the year with three spawning peaks in January, April and September. For the sustainable management of the clam resource in Cat Ba-Ha Long Bay, the fishery authorities can issue a ban on harvest of the clam in spawning peak months in January, April and September. With outstanding universal values, UNESCO recognised Ha Long Bay as World Natural Heritage in 1994 and 2000 and Cat Ba Island as the World Biosphere Reserve in 2014. Karst processes carved hundreds of caves out of the limestone and contributed to the formation of many different unique ecosystems, including lagoons, salt lakes, underground caves, coral reefs, muddy beds, sandy beds, gravel beds and pebble beds. Furthermore, the bay was isolated from mainland for over 18,000 years of its history [Lutraria rhynchaena Jonas, 1844 has been recorded to occur only in waters of Cat Ba-Ha Long Bay of Vietnam and a few surrounding countries such as Philippines, Thailand, China and Australia [Cat Ba-Ha Long Bay is located on the northeast coast of Vietnam. The bay is characterised by karst towers, many large islands and islets <3,000). Of which, Cat Ba is the largest island with the area of 298 km,000. Of ustralia . This spustralia . Althougustralia , artificL. rhynchaena in Cat Ba-Ha Long Bay and (2) to assess their relationship with sediment conditions, temperature and salinity. The timing of clam spawning peaks will be the basis for managers to enact a ban on seasonal or monthly fishing for the clams. The data of distribution and density will be the decisive criteria for the selection of natural clam beds prioritised to protect. For clams that are live buried such as L. rhynchaena, sediment provides the clams with refuge to avoid their predators and drifting by water current. The sediment also helps the clams go to the bottom successfully in the D-shaped larval stage [Area and time restrictions are effective fishery management measures . Of whical stage . Therefo22.1L. rhynchaena and measure water temperature, salinity and sediment characteristics between August 2017 and July 2018 (L. rhynchaena at each study site was monthly estimated from the average of three plots (5 m × 5 m) which were randomly allocated.The study area was located in the littoral and upper sublittoral zone in Cat Ba-Ha Long Bay . In total, 16 sites were chosen to investigate the distribution, density and reproductive cycle of uly 2018 . The den2.2L. rhynchaena specimens were collected monthly during the daytime when the siphons of the clams were clearly visible. Clams were stored in an icebox for transport and subsequent processing in the laboratory. Surface sediment samples were also collected at the 16 sampling sites using a grab sampler and stored in nylon basket pockets in an icebox until grain-size analysis.2.3The temperature and salinity of surface waters were measured monthly at all sites using a thermometer and a refractometer, respectively. Sediment grain size was analysed using a series of sieves for coarse grain (>63 µm) and the pipette method for fine grain (<63 µm) after removing salts and organic matters with distilled water and 10% hydrogen peroxide. A 63 µm sieve was used to separate coarse from fine grains, and then the sediments were dried at 105°C. Coarse grains were further fractionated using a series of sieves with different pore diameters  and weighed. To fractionate fine grains, 5 g was dispersed in NaOH and diluted to 1,000 mL with water, stirred, then sampled over time using a 25 mL pipette to obtain fractions at 63, 31, 16, 8, 4, 2 and 1 µm; excess liquid was evaporated, and grains were dried at 105°C before being weighed [Md) (1), sorting coefficient (S0) (2) and skewness (Sk) (3) according to Folk and Ward (1957) and Folk (1980) [S0  and Sk  reflect the homogeneity of grain size in sediments under influence of current, wave and tide.P5, P16, P50, P84 and P95 is grain diameter at 5%, 16%, 50%, 84% and 95% at the cumulative percentile value, respectively.All sediment fractions were converted into percent and sediment parameters calculated, including mean diameter (k (1980) ,12. Sedik (1980) ,14. All k (1980) . Md refl2.4L. rhynchaena were brought to the laboratory where the visceral mass was removed and fixed in Bouin’s solution for 24 h, then preserved in 70% ethanol. Samples were initially sectioned into slices less than 28 mm thick, dehydrated in 95% ethanol for 4 h, softened in methyl salicylate for 12–24 h, embedded in melting paraffin at 65°C for at least 6 h, sectioned by a microtome into slices of 5–7 µm thick and fixed on glass microscope slides before staining with Hematoxylin Harris for 10 min, rinsed with distilled water for 5 min, then stained with 1% Eosin Y for 12 min. The prepared slides were examined and photographed using a light microscope with attached camera at 400× magnification to determine sex and reproductive stage.A total of 401 individuals of The presence of seminal vesicles containing hair-like spermatozoa in the gonad indicated a male clam, while the presence of follicles with oogonia or polygonal-shaped oocytes indicated a female clam. For hermaphroditic individuals, there were both hair-like spermatozoa and oogonia in the gonad.Clam reproductive maturity was categorised into five stages using the maturity scale described by Cross et al. (2012) , whereby2.5The indifferent stage of development of the female reproductive system was determined when specific inclusions were seen in the follicle cells, and early oocytes were present in the alveolar membrane. The developing stage is recognised by an increasing number and size of oocytes. There is also a central lumen in each follicle into which stalked oocytes protrude. At the ripe stage of development in the female reproductive system, many mature, spherical free oocytes are found within the follicular lumen. At the spawning stage, the number of oocytes decreases and empty spaces in the lumen appear as a result of the release of mature oocytes. Emptying follicles and the cessation of oogenesis in all follicles are characteristics of this stage. At the last stage, the gonads are collapsed and irregular in shape, with big empty spaces in the lumen and few germinal cells.2.6The indifferent stage of development of the male reproductive system is characterised by the presence of aberrant forms of multinucleated non-pyctonic and pyctonic cells. The basal membrane and follicle cells are the dominant structural elements, with a few primary spermatocytes or spermatogonia visible at the periphery of the lumen. In the developing stage, the maturation and proliferation of the spermatocytes take place. In ripe male clams, the follicle is filled with dense radiating bands of spermatozoa with tails which project into the central lumen. At the spawning stage, the follicle is characterised by lower number of spermatozoa compared to the ripe stage. A few spermatozoa remain in the radiating bands, but the rows of follicle cells gradually increase to replace the spawned spermatozoa. At the spent stage in males, the follicles are almost completely filled with follicle cells, and the reduced lumen contains a few sex cells.2.7F-Test Two-Sample for Variances used to examine the variance equal between each pair of samples before T-Test Two-Sample Assuming Equal Variances or T-Test Two-Sample Assuming Unequal Variances was used to compare the difference in mean values of clam’s density between each pair of samples (sampling sites and sediment types). T-Test paired two sample for means was used to compare the difference in mean values of temperature and salinity spatially and temporally.The sex ratio of clams was calculated by dividing the number of female individuals by the number of male individuals. A Chi-squared test was used to determine whether there was a significant difference between the observed female:male sex ratio and the expected female:male sex ratio of 1:1. Single-factor analysis of variance (ANOVA) was used to compare the mean values of temperature and salinity temporally and spatially and examine the effects of location or sediment types on the density of clam with a significance level of 0.05. If the ANOVA was significant, the post-hoc tests were further conducted to compare the difference in mean values between each pair of samples. 33.13.1.1α = 0.05). However, there were no significant differences in temperature between May (2018) and September (2017) , and between May (2018) and October (2017) . The temperature in January was significantly the lowest than those of other months  (α = 0.05), but there was significant difference in salinity seasonally . However, there were no significant differences in salinity among November, 2017 (Nov-17), December, 2017 (Dec-17), January, 2018 (Jan-18) and March, 2018 (Mar-18) , and between October, 2017 (Oct-17) and May, 2018 (May-18)   . The sal = 0.01) . There w = 0.01) .3.2The sedimentary environment consisted of submerged plain, coral reefs and tidal channels. Submerged plain occupied the largest area of the whole Cat Ba-Ha Long Bay region surveyed. Water depth was generally 2–5 m but reached 20 m in the areas of Dau Be and Lan Ha. The benthos was mainly covered by fine silt, and rarely by sand and shell debris.Md of 1176.7 µm, consisting of clastic particles and shell debris. They were very poorly sorted, and the sediment is towards small particles. Very coarse sand + coral reef had Md ranging from 1154.5 to 1560.9 µm, consisting of clastic particles, shell debris, living coral and rock bottom. They were very poorly to poorly sorted, and the sediment was towards small particles and symmetrical. The coarse sands had Md ranging from 581.5 to 757.8 µm, consisting of dead coral particles and shell debris. The coarse sand + coral reef had an Md of 665.6 µm, consisting of sand, shell debris, living coral and rock bottom. Both the coarse sand with and without coral reef were poorly sorted and towards fine skewed and symmetrical. The medium sand had Md ranges from 399.4 to 491.5 µm, was very poorly to poorly sorted and the sediment towards very coarse skewed and fine skewed. The coarse silt had an Md of 21.4 µm, was very poorly sorted and skewed towards very fine. Fine silt had an Md of 6.0 µm and was very poorly sorted  (2 (n = 36) at site No. 12. The second density group was 58.9 ± 25.6 Ind./100 m2 (n = 216) at site No. 08. The third density group ranged from 27.5 ± 11.9 Ind./100 m2 (n = 36) at sites: No. 02, 04, 05, 06, 14 and 15. The fourth density group was 10.7 ± 2.3 Ind./100 m2 (n = 36) at site No. 10. The fifth density group was 6.9 ± 6.0 Ind./100 m2 (n = 36) at site No. 1. The sixth density group was 0.0 Ind./100 m2 (n = 216) at sites: No. 03, 07, 09, 11, 13 and 16.The population density of the clam was low in almost all investigated sites, ranging from 0.0 to 94.7 ind./100 m2 . Based o = 0.01) . The firα = 0.01) (2 (n = 72) in medium sand beds. The second group has the density ranging from 31.3 ± 23.9 Ind./100 m2 (n = 144) in very coarse sand beds and coarse sand beds. The third group has density of 25.0 ± 12.8 Ind./100 m2 (n = 108) in very coarse sand + coral reef bed. The fourth group has density of 10.7 ± 2.3 Ind./100 m2 (n = 36) in coarse sand + coral reef bed. The fifth group has density of 0.0 Ind./100 m2 (n = 108) in coarse silt beds and fine silt beds  . The firilt beds .3.4L. rhynchaena were collected over 12 months from August 2017 to July 2018. The results revealed that 188 (46.88%) were female, 211 (52.62%) were male and two (0.50%) were determined as hermaphrodites. The overall female:male sex ratio was 1:1.12. However, Chi-square test showed that the ratio was not significantly different from a 1:1 ratio . Although statistical tests were not applied to individual months, all months were close to a 1:1 sex ratio with slightly more males than females, with the exception of August and March when there were more females , January (11.11%) and June (11.11%). The percentage of clams at the developing stage ranged from 10.00% to 61.54%, with the lowest percentages being recorded in January (11.11%), April (13.33%) and September (10.00%). The highest percentages at this stage were recorded in November (61.54%), June (38.89%) and October (35.29%). The percentage of clams at the ripe stage ranged from 7.14% to 64.29%, with an average value of 38.75%. The highest percentages were recorded in March (64.29%), August (56.25%) and December (53.33%), whereas the lowest percentage was recorded in May (7.14%). The percentage of clams at the spawning stage ranged from 0.00 to 46.67%, with an average value of 19.74%. The highest percentages were recorded in April (46.67%), September (35.00%) and January (33.33%). In November, spawning clams were not found. The percentage of clams at the spent stage ranged from 0.00 to 57.14%, with an average value of 9.56%, and the highest percentage was recorded in May (57.14%)  .3.6The average percentage of male clams at the ripe stage was highest (31.43%), followed by the developing stage (28.00%), indeterminate stage (18.50%) and spawning stage (15.99%). The percentage of clam at the spent stage was lowest (6.08%). The percentage of clams at the indifferent stage ranged from 0.00 to 42.86%, with the highest percentages being recorded in February (42.86%), October (40.91%), May (31.58%) and June (30.43%); in the remaining months, the percentage was lower than 25.00%. The percentage of clams at the developing stage ranged from 10.53% to 55.56%, with the highest percentages being recorded in November (55.56%) and March (50.00%). The percentage of clams at the ripe stage ranged from 5.26% to 53.30%. The highest percentages were recorded in August (53.33%), December (50.00%) and July (52.63%), whereas the lowest percentages of clams at this ripe stage were registered in May (5.26%), February (21.43%) and October (22.73%). The percentage of clams at the spawning stage ranged from 0.00 to 44.44%, and we failed to find any clams at this stage in October, November or March; in February and July, the percentage of spawning stage clams was low (4.35–7.14%). The highest percentages of clams at the spawning stage were recorded in April (44.44%), January (33.33%) and September (31.82%). The percentage of clams at the spent stage ranged from 0.00 to 31.58%, and we failed to find any clams at this stage in all months with the exception of January (22.22%), April (5.56%), May (31.58%) and September (13.64%) .44.1L. rhynchaena was associated with substrate types in Cat Ba-Ha Long Bay. The clam also inhabited within rock slits on hard bottom, with or without coral covering. On the soft bottom, the clams were only distributed on the following substrate types: sand, coral and shell debris. The clams were not found on coarse silt or fine silt substrate types, although these are the dominant substrate types within the study area. Substrate type influences the distribution of macro-benthic communities [Mya arenaria with burrowing behaviour similar to L. rhynchaena primarily inhabits sand and mud substrates [L. rhynchaena is significantly related to benthic substrate types; the natural clam beds with medium sands could be the best substrate environments for the clam.This study revealed that the distribution of munities ,21,22,23bstrates , with hibstrates . In somebstrates . Certainbstrates . Moreovebstrates . The stu4.2L. rhynchaena in the present study was approximately 1:1.12, slightly more in favour of males but the difference is not significant. The trend that the percentage of male individuals is higher than that of females was previously observed for L. rhynchaena in North Bais Bay, Philippines [L. rhynchaena. However, the hermaphroditism has been described in several other clam species [L. rhynchaena was found in North Bais Bay, Philippines [L. rhynchaena could change according to locally environmental conditions.The female:male sex ratio of lippines , and in lippines ,26,27. W species . The replippines , it was L. rhynchaena over the period of sampling. The presence of gonads in the developing, ripe and spawning stages during most months of the year may suggest that gametogenesis, maturity and spawning of L. rhynchaena occur throughout the year. We observed three peaks of the spawning stage in female clams in September (2017), January (2018) and April (2018). The highest spawning stage peak (46.67%) was in April (2018), which was followed by a very high percentage (57.14%) of spent clams in May (2018), revealing a key spawning event. In January (2018), we have also observed a high percentage of both spawning and spent clams , but there were not any clams in the spent stage in the subsequent month. In September (2017), we have observed a similar trend of gametogenesis development as in January. According to Bantoto and Ilano (2011) [L. rhynchaena also has gonad in developing, mature and spawning stages occurring throughout the year, with two spawning peaks in January and June. The divergence of spawning time was also recorded for other clam species (e.g. Mya arenaria and Marcia optima). In Skagit Bay, Washington, USA, spawning of Mya arenaria lasts from late May to early August, with its peak in June–July [Marcia optima has been recorded from May to July in the south-east, while in the south-west, it is from March to May [All five stages of gametogenesis were observed in rcentage 7.14% of une–July . In Capeune–July . In eastune–July . On the h to May .Mya arenaria [Mya arenaria peaks in the months after water temperatures reaches its highest [Meretrix lusoria in Ariake Sound and Tokyo Bay in Japan [L. rhynchaena in the Philippines. An increase of 5°C of water temperature, from 27°C in January to 32°C in June, could have triggered the spawning of the clam which peaked in June. Similarly, the decrease of 3.1°C from 32°C in June to 28.9°C in December might make it possible for gonads to mature, resulting in another spawning peak in January. The study results of Hwang (2007) [Pinctada fucata and Pinctada margaritifera exhibited different annual cyclical patterns, in which maturity peaked in May and October for P. fucata, and in July and November for P. margaritifera. Spawning peaks of P. fucata were synchronised with rising and decreasing temperatures in May and October. In the current study, L. rhynchaena had three spawning peaks in April, September and January, with the highest peak in April. With respect to temperatures, only the spawning peak in January is synchronised with the “critical” temperature, the lowest one; the two remaining spawning peaks occurred during rising and decreasing temperature events. However, April and October are transition months of the northern monsoon and southwest’s wind. The northern monsoon lasts from November to March, and the southwest’s wind lasts from May to September. During the northern monsoon, the climate is cold with less rain, but during periods with southwesterly winds, the climate is hot and rains heavily. Seasonal temperature changes likely trigger maturation and spawning of L. rhynchaena in Cat Ba-Ha Long Bay. For the sustainable management of the clam resource in Cat Ba-Ha Long Bay, the fishery authorities can issue a ban on harvest of the clam in spawning peak months in January, April and September.It is noteworthy that the percentage of clams in the ripe stage of maturity was often high throughout the year, with the exception of the month following the peak-spawning month. It seems that gametogenesis of clams was affected by local environmental conditions. In temperate waters, rising temperatures in summer months can synchronise the ripe and spawning stages of bivalve molluscs ,34,35,36arenaria . Spawnin highest . Temperain Japan . In tropin Japan . Accordi


The current analysis was performed to estimate the percentage and number of Chinese adults with hypertension and the percentage and number of Chinese adults recommended to receive pharmacological antihypertensive treatment according to the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline compared with the same parameters according to the 2010 Chinese guideline.We used 2011 data from the China Health and Nutrition Survey (CHNS). A total of 12,499 Chinese adults aged ≥18 years with complete blood pressure (BP) values were selected for the present analysis.The crude prevalence rates (95% CI) of hypertension according to the definitions from the 2017 ACC/AHA guideline and the 2010 Chinese guideline were 58.0% (57.2 to 58.9%) and 25.4% (24.7 to 26.2%), respectively. Moreover, the percentage of the participants recommended to take antihypertensive medications were 31.5 and 28.8%, respectively. Among adults who took antihypertensive medications, 88.8% had above-goal BP levels compared to 53.3%. Overall, 613.3 million Chinese adults (aged ≥18 years) met the criteria for hypertension according to the 2017 ACC/AHA guideline, and 267.7 million met the criteria according to 2010 Chinese guideline. An additional 28.4 million (2.7%) Chinese adults were recommended to take antihypertensive medication.The present analysis revealed that the 2017 ACC/AHA hypertension guideline will result in a substantial increase in the percentage and number of Chinese adults defined as having hypertension and a small increase in the percentage of adults who are recommended to take antihypertensive medications compared to the same parameters based on the 2010 Chinese guideline. More intensive management and antihypertensive medications use are suggested to improve the control rate of hypertension among Chinese adults. On November 13, 2017, the American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults was published , while categorical variables were expressed as counts and percentages (%). We calculated the distribution of the Chinese adults across five groups, including four groups that did not take antihypertensive medication  and a group taking antihypertensive drugs. Patient groups were compared by P < 0.001).The median age of the present study participants was 51.0 ± 15.2 years, and 53.3% were women. A total of 13.4% (1663) of Chinese adults were taking antihypertensive medications. A total of 32.0, 9.7, 30.1 and 14.6% of Chinese adults not taking antihypertensive medications had SBP/DBP levels of < 120/80, 120–129/< 80, 130–139/80–89, and ≥ 140/90 mmHg, respectively (Table P < 0.05)  of hypertension according to the definitions from the 2017 ACC/AHA guideline and the 2010 Chinese guideline were 58.0% (57.2 to 58.9%) and 25.4% (24.7 to 26.2%), respectively Table . The pre5) Table .Table 3The percentage of individuals recommended to take antihypertensive medications among Chinese adults was 31.5 and 28.8% according to the 2017 ACC/AHA guideline and 2010 Chinese guideline, respectively. An increase in the percentage of the population recommended to take antihypertensive medication based on the 2017 ACC/AHA guideline compared to that based on the 2010 Chinese guideline was present in all subgroups. The subgroups of individuals with an older age and a history of CVD had a relatively higher increase relative to adults with a young age and without CVD history Table . Among CIn 2011, 613.3 million Chinese adults (≥ 18 years) met the criteria for hypertension according to the 2017 ACC/AHA guideline compared with 267.7 million Chinese adults according to the 2010 Chinese guideline Table . Using tAmong these Chinese adults taking antihypertensive medications, 88.8% had above-goal BP according to the 2017 ACC/AHA guideline compared to 53.3% with above-goal BP according to the 2010 Chinese guideline Table . AdditioThe present analysis indicates the potential impacts of the 2017 ACC/AHA guideline on the definition of hypertension, recommendation for antihypertensive medication in addition to nonpharmacological interventions and blood pressure goals in individuals receiving antihypertensive drug treatment among Chinese adults . In addition, the control rate of hypertension will decrease sharply from 46.7 to 11.2% among adults taking antihypertensive medications. It is important to determine how to address the 2017 ACC/AHA hypertension guideline? We should pay more attention to the positive impact of the 2017 ACC/AHA guideline and perform some cost-effectiveness analyses regarding the implementation of the guideline. Regardless, we should positively consider the control and management of hypertension, based on the real policies of China to further reduce the burden of CVD in China.


Conus textile belongs to the family Conidae. It is a kind of molluscivorous species. The complete mitochondrial DNA sequence was constructed by next-generation sequencing in this study. The mitogenome of C. textile is 15,765 bp in length, including 13 protein-coding genes, 22 tRNA genes, 2 ribosomal RNA genes and 1 control region. The base composition was 27.3% A, 37.9% T, 15.7% C and 19.1% G. The phylogenetic tree of C. textile with the other 6 Conus species and 15 Neogastropoda sea snails was built. It provides fundamental data for further research of phylogeny and biogeography with this genus.The cone snail  Conus) are a species-rich genus of venomous marine gastropods. They inject their venom through a hypodermic needle-like radula harpoon that can penetrate deep into the dermis of their prey . Their venoms consist of complex venoms composed mostly 100–250 disulfide-bridged peptides . We present the complete mitochondrial genome sequence of C. textile  in this study were collected from north coast of Taiwan . They are very common species in that area. The samples were deposited in Marine Toxins Lab., Department of Food Science, National Taiwan Ocean University, Taiwan. The total genomic DNA was extracted from muscle using magnetic bead technique with the KingFisher magnetic processors . The raw next-generation sequencing reads generated from MiSeq sequencer  were de novo assembled and reference mapping was conducted by commercial software  to produce a single circular form of complete mitogenome with about an average 24.3 coverage . The complete mitochondrial genome of C. textile is 15,765 bp in size, including 13 protein-coding genes, 22 tRNA genes, 2 ribosomal RNA genes (12S and 16S rRNA) and 1 control region. The overall base composition of C. textile is 27.3% for A, 37.9% for T, 15.7% for C and 19.1% for G. The protein coding rRNA and tRNA genes of C. textile mitogenome were predicted by using MITOS (Bernt et al. The specimens of C. textile and related families by Neighbor-joining method with 1,000 bootstrap replicates based on the 13 protein-coding genes and 2 ribosomal RNA genes of the other 21 complete mitochondrial genomes of Neogastropoda sea snails, which are reported in Genbank of NCBI database. Bootstrap support values were relatively high, with 13 nodes having values >95% and 8 nodes demonstrating 100% bootstrap support (C. textile was grouped together with other six Conus species from the family Conidae. The lineages of Conidae strongly supported in this report and agreed with previous studies (Bouchet et al. We used MEGA 6 (Tamura et al.  support . C. text


Among men who have sex with men (MSM) and transgender women (TW), stimulant use is high and has been associated with an increased risk of HIV infection, suicide and cardiovascular disease (CVD) mortality. We used epidemic modelling to investigate these intersecting health harms among MSM/TW in Lima, Peru and assess whether they could be mitigated by prioritizing HIV pre‐exposure prophylaxis (PrEP) and harm reduction interventions among MSM/TW who use stimulants.We adapted a dynamic model of HIV transmission among MSM/TW in Lima to incorporate stimulant use and increased HIV risk, suicide and CVD mortality. Among 6% to 24% of MSM/TW using stimulants (mostly cocaine), we modelled an increased risk of unprotected anal sex (RR = 1.35 [95%CI: 1.17 to 1.57]) obtained from local data, and increased risk of suicide (SMR = 6.26 [95%CI: 2.84 to 13.80]) and CVD (SMR = 1.83 [95%CI: 0.39 to 8.57]) mortality associated with cocaine use based on a global systematic review. We estimated the proportion of health harms occurring among MSM/TW who use stimulants in the next year (01‐2020/01‐2021). We also investigated the 10‐year impact (01‐2020/01‐2030) of: (1) PrEP prioritization for stimulant‐using MSM/TW compared to random allocation, and (2) integrating PrEP with a theoretical intervention halving stimulant‐associated risk.MSM/TW in Lima will experience high HIV incidence, suicide mortality and CVD mortality  in 2020. Despite stimulant using MSM/TW comprising an estimated 9.5% (95%CI: 7.8 to 11.5) of all MSM/TW, in the next year, 11% 95%CI (i.e. 2.5% to 97.5% percentile) 10% to 13%) of new HIV infections, 39% (95%CI: 18% to 60%) of suicides and 15% (95%CI: 3% to 44%) of CVD deaths could occur among this group. Scaling up PrEP among all stimulant using MSM/TW could prevent 19% (95%CI: 11% to 31%) more HIV infections over 10 years compared to random allocation. Integrating PrEP and an intervention to halve stimulant‐associated risks could reduce new HIV infections by 20% (95%CI: 10% to 37%), suicide deaths by 14% (95%CI: 5% to 27%) and CVD deaths by 3% (95%CI: 0% to 16%) over a decade.MSM/TW who use stimulants experience a disproportionate burden of health harms. Prioritizing PrEP based on stimulant use, in addition to sexual behaviour/gender identity criteria, could increase its impact. Integrated substance use, harm reduction, mental health and HIV care among MSM/TW is needed. Higher While there are no approved medications to treat either cocaine or meth/amphetamine dependence , harm reEpidemic modelling can be used to quantify the contribution of groups to intersecting epidemics, and the potential population‐level impact of interventions, thereby guiding evidence‐based policymaking . As in m22.1We modified a previously published epidemic model of HIV transmission among MSM and TW in Lima, Peru , to inco2.2The model was mainly parameterized using data from multiple local MSM/TW surveillance rounds, local epidemiological studies and global reviews and meta‐analyses. Regarding stimulant use, the 2011 surveillance round among MSM/TW is the most recent source of comprehensive drug use and sexual behaviour data among MSM/TW in Peru. Using these data, we calculated the prevalence of stimulant use in the past 3 months in each group in Lima, corresponding to 6.2% (95%CI: 4.6 to 7.8) among homosexual identified MSM, 13.3% (95%CI: 10.6 to 16.1) among heterosexual/bisexual identified MSM, 23.61% (95%CI: 20.7 to 26.5) among MSW and 17.8% (95%CI: 14.3 to 21.4) among TW. Virtually all MSM/TW (98%) who reported stimulant use were using cocaine and/or cocaine paste   associated with suicide among people who use cocaine obtained from a recent global systematic review   was simulated with 10,000 different parameter sets randomly sampled through Latin hypercube sampling. The log likelihood of each simulated epidemic trajectory was calculated based on time series HIV prevalence data from 1985 to 2011 for the total MSM/TW population and for each group , time series HIV incidence data from 1999 to 2014 for the total MSM/TW population (5 data points), the proportion using stimulants per group in 2011 and the total ART coverage for 2011 : ςk,ft=Xk,21/∑fXk,f1 corresponding to the proportion using stimulants in each group.Scenario 2 : ςk,ft is the PrEP coverage at time point (t) among those in sexual behaviour group k and stimulant use group f  and Xk,f1 corresponds to the number of susceptible individuals in each sexual behaviour/stimulant use group.Where 2.6Due to a lack of effective treatment for stimulant use, we simulated the potential benefits of a hypothetical harm reduction intervention package assumed to reduce the excess risks of HIV, suicide and CVD mortality associated with stimulant use by half. This could be as a result of decreases in the intensity/frequency of stimulant use or through combined harm reduction interventions including condom use distribution and promotion, psychological/psychiatric treatment to prevent suicide and CVD treatment to prevent CVD mortality.2.72.7.1While evidence is mixed , some st2.7.2We performed a sensitivity analysis assuming turnover between groups using and not using stimulants, with an average duration of stimulant use of 5 years.2.7.3We assumed a two to sevenfold higher rate of suicide among MSM  and a one to threefold higher rate among TW compared to MSM, to acknowledge evidence of higher suicide rates among these populations.2.7.4We implemented a scenario in which 100% of TW would be covered, with the remainder given to MSW to compare the effectiveness of this established strategy to that of PrEP prioritization by stimulant use.33.1Our model estimates MSM and TW in Lima experience a high burden of HIV incidence, suicide mortality and CVD mortality, with estimates of 1.63 per 100 person‐years (/100 py) : 0.83 to 2.51), 0.018/100 py (95%CI: 0.008 to 0.040) and 0.13/100 PY (95%CI: 0.03 to 0.5), respectively, in 2020.The burden of each of these health harms differs by group, with 7.1% (95%CI: 4.7 to 10.0), 5.6% (95%CI: 3.6 to 8.7) and 4.7% (95%CI: 3.3 to 7.1) of new HIV infections, suicide deaths and CVD deaths, respectively, occurring among TW when they comprise 4.5% (95%CI: 2.9% to 6.7%) of the total MSM/TW population and 12.4% (95%CI: 8.7 to 16.9), 12.2% (95%CI: 4.2 to 22.9) and 9.0% (95%CI: 3.3 to 17.2) of new HIV infections, suicide deaths and CVD deaths, respectively, occurring among MSW when they comprise 8.3% (95%CI: 3.4% to 15.0%) of the total MSM/TW population. The ratios of the proportion of HIV infections, suicides and CVD deaths among each group in one year divided by the proportion of individuals in each group are shown in Figure 3.2Our modelling indicates that despite MSM/TW who use stimulants comprising an estimated 9.5% (95%CI: 7.8 to 11.5) of the overall MSM/TW population in Lima, between 2020 and 2021, 11% (95%CI: 10% to 13%) of new HIV infections, 39% (95%CI: 18% to 60%) of suicides and 15% (95%CI: 3% to 44%) of CVD deaths would occur among this group. The ratios of the proportion of HIV infections, suicides and CVD deaths among MSM/TW who use stimulants by the proportion of MSM/TW in this group are shown in Figure 3.3Scaling up PrEP among all (100%) MSM/TW who use stimulants in each group between 2020 and 2030 would prevent 17.9% (95%CI: 9.1 to 34.9) of new HIV infections  of new HIV infections, 14% (95%CI: 5% to 27%) of suicide deaths and 3% (95%CI: 0% to 16%) of CVD deaths between 2020 and 2030  more effective, compared to 19% (95%CI: 11% to 31% with no adherence differences).Assuming a five‐year duration of stimulant use, the proportion of new HIV infections occurring among MSM/TW who use stimulants was virtually unchanged at 11.1% (95%CI: 9.7% to 13.3%) and the relative increased impact of the PrEP prioritization scenario was 17% (95%CI: 9% to 31%) under this shorter duration of stimulant use (vs. 19% (95%CI: 11% to 31%) at baseline), indicating a strategy of prioritization by stimulant use may be slightly less effective under shorter durations of stimulant use.Assuming higher suicide rates among MSM (two to sevenfold) and TW (one to threefold higher than among MSM), translated to a suicide incidence of 0.08/100 py (95%CI: 0.02 to 0.19) versus 0.018/100 py  of suicide deaths (vs. 5.6% (95%CI: 3.6% to 8.7%) at baseline) occurring among TW  reduction in new HIV infections between 2020 and 2030, which is 23% greater than obtained through the prioritization strategy based on stimulant use.4Our study quantified the burden of HIV, suicide mortality and CVD mortality in association with stimulant use among MSM and TW in Lima, Peru. We chose Peru as a useful case study due to the high prevalence of HIV and stimulant use among MSM and TW, comparable to other global settings. We found that MSM/TW who use stimulants are disproportionately affected by incident HIV infection, suicide mortality and CVD mortality. In addition, male sex workers and TW had a higher burden of these health harms compared to homosexual and heterosexual/bisexual MSM (who do not engage in sex work) due to increased sexual risk behaviours and stimulant use. Indeed, substance use among TW in Lima has been described , 56 as pBox 1Our modelling indicates that PrEP prioritization for MSM/TW who use stimulants could increase its impact in Lima, even with potentially lower PrEP adherence among this group. In practice, this would entail integrating substance use and sexual risk assessment within one clinical visit when prescribing PrEP, which currently does not happen systematically. More importantly, even when questions on substance use are asked, this information is rarely acted upon, meaning that referral to substance use counselling, treatment, or harm reduction strategies are not delivered. In this study, we also showed that providing harm reduction interventions in combination with PrEP among MSM/TW who use stimulants would result in substantial overall reductions in HIV, suicide and CVD mortality. Our sensitivity analysis showed that given higher HIV incidence among TW and MSW, a PrEP prioritization strategy based on gender identity/sexual behaviour would have a larger impact compared to a prioritization strategy by stimulant use, but overall our study suggests that stimulant use should be included as an additional criterion in current guidelines  see Box. ImportaTo our knowledge this is the first modelling study examining the impact of stimulant use among MSM/TW on HIV, suicide and CVD, but it supports recent modelling highlighting the excess risks of stimulant use on HIV and related infections among PWID . The estBox 2Our study has limitations. First, like all models ours was limited by data uncertainties. For example we lacked MSM/TW and setting‐specific data on suicide and CVD mortality overall and by stimulant use. As a result, our model might underestimate overall infection/mortality burden and dilute differences between groups. While we implemented a sensitivity analysis to address this in relation to suicide rates, the study should be updated when MSM/TW‐specific data become available see Box . ImportaSecond, we simulated a theoretical intervention package as there are no effective pharmacotherapies for stimulant use, and psychosocial therapies have weak or nonspecific effects. Our study therefore presents the potential impact if a stimulant use treatment were developed, or if a package of interventions were provided to address HIV, suicide and CVD among MSM/TW who use stimulants. Studies have shown low to moderate effectiveness of psychosocial interventions including motivational interviewing, contingency management and cognitive behavioural therapy, on reducing both methamphetamine use and risky sexual behaviours among MSM . Among TThird, while our model incorporates much complexity in terms of sexual behaviours and stimulant use by sexual orientation, gender identity and engagement in sex work; a full range of intersecting health risks exists that we did not explore. Associations between HIV infection and suicidality have been consistently reported. Similarly, there is evidence for higher risk of CVD among HIV‐positive patients , 67, 68.5Our modelling indicates that prioritization of HIV PrEP among MSM/TW in Lima who use stimulants could enhance PrEP prioritization strategies based on sexual behaviours, or sexual orientation/gender identify. Stronger integration of interventions that address stimulant use among MSM/TW in HIV programmes is key to reducing multiple associated harms among this population. Importantly, these interventions should be complementary to broader interventions addressing the vulnerabilities and structural gaps that affect the wellbeing of sexual minorities in Peru. Interventions to guarantee their fundamental rights, including the right to an official identification reflecting their gender, the right to protection from harassment and violence, and the right to employment and health, are key to reducing persistent health disparities.NM has received unrestricted research grants from Gilead and Merck unrelated to this work. All other authors declare no competing interests.AB and NM conceptualized the study analyses and wrote the first draft of the manuscript. AB developed the model and generated model results and figures. LT, LD, RM, SK and MF conducted the systematic reviews and meta‐analyses to inform model parameterization. RA provided data to inform the model and provided guidance in its analyses and interpretation of results. KR and KK conducted statistical analyses to inform the model parameterization. CC, AS and JC aided in manuscript drafting. All authors critically reviewed and approved the manuscript for submission.Integrating services for HIV and related comorbidities: modelling to inform policy and practice Supplement was supported by the US National Institutes of Health, Fogarty International Center. Additional support was provided by the National Institute on Drug Abuse , the National Institute of Allergy and Infectious Diseases (R01AI147490 [NM]), the Australian National Drug and Alcohol Research Center [MF], the National Health and Medical Research Fellowship [LD], the Curtin Senior Research Fellowship [RM], UNITAID through the ImPrEP study [CC] and [KK].This article as part of the Appendix S1. Model specifications, equations, parameterization and analyses.Click here for additional data file.


The use of antibiotics is known to alter the gut microbiome and it is hypothesised that the use of antibiotics may also alter the response to immune checkpoint inhibitors (ICI). As data is limited from real-world settings, we performed a retrospective audit of patients who received ICI along with concomitant antibiotics.This study is a retrospective audit of a prospectively collected the database of patients who received ICI for advanced solid tumours in any line between August 2015 and November 2018 at Tata Memorial Hospital, Mumbai, India. Antibiotic use was recorded from 2 weeks before the start of ICI and concomitantly with ICI. All statistical calculations were performed using Statistical Package for the Social Sciences (SPSS) statistical software for windows version 20.0.p = 0.912). Median OS in the patients who received antibiotics was 3.9 months (95% CI: 1.8–11.4) as compared to 9.2 months (95% CI: 4.2–12.3) who did not receive antibiotics p = 0.053 . Among the patients who received antibiotics, median OS for patients who received ≤10 days of antibiotics was 8.8 months (95% CI: 4.2–11.2) while for patients receiving >10 days of antibiotics, it was 2.8 months (95% CI: 1.2–4.4), p = 0.025 . Thirty-three  patients received antibiotics during the window of 2 weeks before the start of ICI to 2 months of starting ICI. Median OS in the patients who received antibiotics in this window was 2.8 months (95% CI: 1.2–4.5) as compared to 9.2 months (95% CI: 5.2–13.1) who did not receive antibiotics p = 0.008 .A total of 155 patients were identified as having received ICI during the study period, out of which 70 (44%) patients received antibiotics. Median PFS in patients who received antibiotics was 1.7 months (95% CI: 1.1–2.3) as against 3.6 months (95% CI: 2.3–4.8) for patients who did not receive antibiotics (This study shows that the judicious use of antibiotics is required in patients on ICI or scheduled to be started on ICI. Gopalkrishnan et al [The human gut microbiota represents a complex and interconnected ecosystem composed of trillions of microorganisms living within the human gut . Preclinet al , a negatet al . Anotherl [et al  studied an et al  prospectThis study is a retrospective audit of a prospectively collected the database of patients who received ICI for advanced solid tumours in any line between August 2015 and November 2018 at Tata Memorial Hospital, Mumbai, India. Antibiotic use  for at least 5 days was recorded from 2 weeks before the start of ICI and concomitantly with ICI. Also, an additional analysis was performed to evaluate the use of antibiotics during the window of 2 weeks before to first 2 months versus other patients receiving ICI. The choice of antibiotics was based on the clinical and radiological focus for infection at presentation and subsequently modified based on response and culture reports. Steroid use was considered significant if patients received prednisolone equivalent of ≥10 mg per day for any duration. This particular threshold was in accordance with the exclusion criterion of most of the pivotal immunotherapy clinical trials . All theThe response assessment was performed using radiological assessment according to the Response Evaluation Criteria in Solid Tumours version 1.1. Response assessment was done 2 months after the commencement of ICI or at any symptoms/signs of clinical progression whichever was earlier. Adverse events during immunotherapy were documented and graded using the Common Terminology Criteria for Adverse Events, version 4.02. PFS was defined as the interval from the date of starting ICI till the date of progression or death due to any cause if it occurred before disease progression or the last follow-up date whichever was earlier. OS was calculated from the date of the start of ICI to date of death. Patients who were still alive were censored at the date of the last contact.p values were based on a two-sided hypothesis with confidence interval (CI) at the 95% level, and p < 0.05 was considered as statistically significant. All statistical calculations were performed using SPSS statistical software for windows version 20.0 .Descriptive statistics were used to summarise categorical and continuous variables. Time-to-event analysis was done using the Kaplan–Meier estimator and hazard ratio was calculated by using the Cox proportional model. A two-way analysis of variance was conducted that examined the effect of use of steroids and use of antibiotics on the overall survival. All A total of 155 patients were identified to have received ICI during the study period out of which 70 (44%) patients received antibiotics. All these patients had received nivolumab as ICI. p = 0.912). Median OS in the patients who received antibiotics was 3.9 months (95% CI: 1.8–11.4) as compared to 9.2 months (95% CI: 4.2–12.3) who did not receive antibiotics p = 0.053 . The percentage of patients surviving at 12 months who didn’t receive antibiotics was 39.4% (±6.7) versus 36.2% (±6.4) for those who received antibiotics. Among the patients who received antibiotics, median OS for patients who received ≤10 days of antibiotics was 8.8 months (95% CI: 4.2–11.2) while for patients receiving >10 days of antibiotics, it was 2.8 months (95% CI: 1.2–4.4), p = 0.025 . For urothelial carcinoma as primary, median OS was 5 months . On univariate analysis, performance status, use of steroids and duration of antibiotics use came as significant factors and all the three factors were found to be significant in the multivariate analysis also . There was no significant difference in survival based on the class of antibiotics used, gender, age, site of primary, line of therapy and presence of brain metastasis. There was a statistically significant interaction between the effects of use of steroids and use of antibiotics on the overall survival, F  = 5.9, p =0.016 (The median follow up duration was 9.5 months (95% CI: 6.8–12.2). Median PFS in patients who received antibiotics was 1.7 months (95% CI: 1.1–2.3) as against 3.6 months (95% CI: 2.3–4.8) for patients who did not receive antibiotics . The percentage of patients surviving at 12 months who didn’t receive antibiotics in this particular time-window was 41.8% (±5.7) versus 22.5% (±7.4) for those who received antibiotics.Thirty-three  patients received antibiotics during the window of 2 weeks before the start of ICI to 2 months of starting ICI. Median OS in the patients who received antibiotics in this window was 2.8 months (95% CI: 1.2–4.5) as compared to 9.2 months (95% CI: 5.2–13.1) who did not receive antibiotics et al [In a systematic review by Elkrief et al , 11 out In our study, we included patients who received antibiotics up to 2 weeks before the start of ICI. Previous studies have suggested a time-dependent and partial repopulation of the gut microbiota after discontinuation of antibiotics . In the In our study, we found that a longer duration of antibiotics use was associated with poorer clinical outcomes and this was independent of performance status. Another important finding in our study was statistically significant better OS in patients who did not receive steroids versus those who did. To our knowledge, no previous study has reported results on the use of steroids in patients who received antibiotics while receiving ICI. Thus, our study adds important information on the interaction of the use of both antibiotics and steroids in patients receiving ICI. This interaction was found to be statistically significant affecting the overall survival. Another important strength of this study being the use of single ICI in fairly large number of patients as against other studies which report the use of multiple ICIs in smaller cohorts of patients. Besides, this study demonstrated statistically significant interaction between the effects of use of steroids and use of antibiotics on the overall survival.There are some important drawbacks of the study; apart from the retrospective nature of the study, this study included principally patients of NSCLC and head neck cancers. This may preclude the broad application of results to every solid tumour treated with ICI. Also, breaking down the data into various sub-groups might have led to non-significant results making interpretation difficult. Despite these limitations, this study adds important real-world data on the use of antibiotics concomitant with ICI.This study shows that the judicious use of antibiotics is required in patients on ICI or scheduled to be started on ICI. However, more data is required for recommending postponement of initiation of ICI which would allow a spontaneous recovery from antibiotic mediated dysbiosis.The authors have no conflicts of interest to declare.The authors or institution did not receive any funding for this research.Conception and design: Vanita Noronha, Kumar Prabhash. Provision of patients: Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Amit Joshi, Nandini Menon, Kumar Prabhash. Collection and assembly of data: Akhil Kapoor, Abhishek Mahajan, Amit Janu. Data analysis and interpretation: Akhil Kapoor, Vanita Noronha, Kumar Prabhash. Manuscript writing: All authors. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors.


A retrospective study was conducted to assess the mediation role of low birth weight, and low ponderal index between the preeclampsia, placenta previa, and neonatal mortality in the tertiary hospital of Hubei Province, China.A total of 12772 neonatal births were included for data analysis. Birth weight, birth length, and neonatal mortality were recorded after birth. Sobel test based on mediation regression was used to evaluate the effect of mediator variables.Approximately, 383 (3%) and 409 (3.2%) women experienced preeclampsia and placenta previa respectively. After adjusting for covariates, the indirect effect of preeclampsia on neonatal mortality mediated by low birth weight and low ponderal index was [β 2.59 (95% CI: 0.74 – 4.44)], and [β 3.94 (95% CI: 1.50 – 6.38)] respectively. Moreover, the indirect effect of placenta previa on neonatal mortality mediated by the low birth weight was [β 1.74 (95% CI: 0.16 – 3.31)], and low ponderal index was [β 3.21 (95% CI: 0.95 – 5.48)]. The estimated mediation proportion between the preeclampsia and neonatal mortality accounting for possible mediation by low birth weight and low ponderal index was 44.5% and 34.5% respectively. Furthermore, 47.9% by low birth weight and 33.2% by low ponderal index mediate the association between placenta previa and neonatal mortality.Low birth weight, and low ponderal index partially mediates the association between preeclampsia, placenta previa and neonatal mortality. Neonatal mortality is an essential indicator for determining the neonatal health status of a country . GloballPreeclampsia is one of the potential causes of maternal and neonatal mortality and morbidity . It affeNeonates with low birth weight (LBW) are approximately, 20 times more likely to die than heavier neonates . LBW remTo the best of our knowledge, mediating effect of LBW, LPI between preeclampsia, placenta previa, and neonatal mortality has not examined before in Hubei, China. Therefore, the present study aimed to examine the extent to which low LBW and LPI mediates the association between preeclampsia, placenta previa, and neonatal mortality.A tertiary hospital-based retrospective study was conducted in the Wuhan University Renmin Hospital, Department of Obstetrics and Gynecology, Hubei, China from January 2011 to March 2017. All the data was collected and documented in obstetrics register by trained nurses during individual medical examination. We excluded 308 with missing data on maternal age, prepregnancy body weight, and neonatal gender . A totalWe included singleton full-term neonates (≥37 weeks) and excluded twins (n=970), preterm (<37 weeks) (n=2450), maternal, and incomplete neonatal record from the data analysis.3×100. The ponderal index between 2.5 and 3.0 was considered normal, between 2.0 and 2.5 marginal, and a neonate with ponderal index less than 2.0 was considered a LPI. Neonatal mortality is defined as the death of neonate occurs in (0–28 days) after neonatal birth. The neonatal mortality rate was determined by a number of neonatal deaths/number of live births×1000. The Apgar score was determined by evaluating the newborn baby on five simple criteria on a scale from zero to two, then summing up the five values obtained. The Apgar score was recorded at 1 and 5 minutes after birth.Pre-eclampsia (PE) defined as the onset of high blood pressure (≥140/90mmHg) and often a significant amount of protein (≥0.3 mg/dL) in urine after 20 weeks of gestation. Placenta previa referred to when the placenta attaches inside the uterus but near or over the cervical opening. LBW is defined as birth weight < 2500g. The ponderal index was determined by weight in gm / (length in cm) The study was approved by the Ethical Review Board of Renmin Hospital (ID: WDRY2019–K034) Wuhan university in accordance with the Declaration of Helsinki.We used mediation analysis. In this analysis, the major focus is to determine that how an intermediated variable (mediator/M) mediates the effect of predictor variable (PV) on an outcome variable (OV) . Hence, According to the Baron and Kenny statistical mediation approach , the totc) represents the TE (sum of DE and ME) of PV on OV and c′ represents the ME of PV on OV with M included as a covariate, which is obtained from . The 95% confidence intervals for the ME were calculated by the bootstrap approach  and R software.The ME was estimated by multiplying the regression coefficient of the effect of the PV on the M from Model 2/M2 and Model 3/M3 with the regression coefficient of the effect of the M on the OV from Model 4/M4 , 37. Onend Kenny . Whereasapproach , 39. P <Our analysis consisted of a total 12772 women. Around, 383 (3%) and 409 (3.2%) women experienced preeclampsia and placenta previa respectively. Neonates born with LBW were 358 (2.8%) while, 294 (2.3%) were born with a LPI. Almost, 12005 (94%) neonates had normal (>7), 510 (4%) intermediate (4–6), and 257 (2%) low (0–3) APGAR score. The neonatal mortality rate was found at 8.7 per 1000 live birth .The Sobel test results showed LBW and LPI mediate the association between preeclampsia, placenta previa, and neonatal mortality .The adjusted odds ratio (aOR), and p-value from the regression models  are shown in From the mediation regression analysis, we observed ME of preeclampsia on neonatal mortality mediated by LBW and LPI was [β 2.59 (95% CI: 0.74 – 4.44)], and [β 3.94 (95% CI: 1.50 – 6.38)] respectively. Moreover, the ME of placenta previa on neonatal mortality mediated by LBW was [β 1.74 (95% CI: 0.16 – 3.31)], and LPI was [β 3.21 (95% CI: 0.95 – 5.48)]. The estimated MP between preeclampsia and neonatal mortality accounting for possible mediation by LBW and LPI was 44.5% and 34.5% respectively. Furthermore, 47.9% by LBW and 33.2% by LPI mediates the association between placenta previa and neonatal mortality .To study the association between PV and OV, there are certain conditions in which the PV affects the OV both directly and indirectly, through an intermediate variable (M), which further influences OV. Therefore, considering mediators in statistical analysis enables researchers to fully understand the complex association between variables.In patients with preeclampsia, the utero-placental blood perfusion drops to 50–60 % after 3 to 4 weeks of the complication. A shallow trophoblastic invasion of the decidual arteries can cause pre-eclampsia, and the hypo-uteroplacental flow cause insufficient transport of the nutrients. It is intuitive that hypo-uteroplacental blood flow should induce decreased fetal growth, with an increased risk of LBW and intrauterine growth restriction .P< 0.05) increased the risk of LBW and LPI. A significant negative association between the preeclampsia and neonatal LBW is reported  increased the risk of neonatal mortality. Among obstetric complications, preeclampsia was the leading cause of neonatal mortality . AnotherPlacenta previa is one of the abnormal forms of placentation that hurts fetal wellbeing due to morbidity and perinatal mortality, in particular, its undesirable effect on fetal growth . Some faP<0.05) the risk of LBW and LPI. The association between placenta previa and LBW is mainly due to the influences of preterm birth, and virtually very little due to impaired fetal growth (We observed that placenta previa significantly increased (l growth . Howeverl growth –29. The P<0.05) risk factor of neonatal mortality. Prior studies have reported contradictory results on the association between placenta previa and neonatal mortality , infection, asphyxia, and neonatal respiratory distress syndrome . MoreoveTo eliminate the effect of preterm birth and twins on the LPI, LBW, and neonatal mortality, we confined our analysis to only singleton term birth, which is the potential selection bias in our analysis. The study was conducted in only one tertiary hospital. So, our results cannot be generalized to the whole population.LBW and LPI partially mediate the association between preeclampsia, placenta previa, and neonatal mortality. Furthermore, large population-based study is required to confirm our results.Ethical issues  have been completely observed by the authors.


Background: Wearable electrochemical sensors that detect human biomarkers allow a comprehensive analysis of a person’s health condition. The “electronic smart patch system for wireless monitoring of molecular biomarkers for health care and well-being” (ELSAH) project aims to develop a minimally invasive sensor system that is capable of continuously monitoring glucose and lactate in the dermal interstitial fluid in real time. It is the objective of the present study to compare the intended ELSAH-patch specifications with the expectations and requirements of potential end-users at an early stage during the development phase. Methods: A questionnaire addressing different aspects of the ELSAH-patch was filled out by 383 respondents. Results: The participants stated a high general demand for such a system, and they would use the ELSAH-patch in different health care and physical fitness applications. The preferred terminal device for communication with the sensor would be the smartphone. An operating time of 24 hours would be sufficient for 55.8% of the users (95%-CI: 50.3–61.3%), while 43.5% of them (95%-CI: 38.0–48.9%) would prefer a lifetime of several days or more. The software should have a warning function, especially for critical health conditions. Since the measured personal data would be highly sensitive, the participants called for high standards for data security and privacy. Conclusion: In general, the participants’ responses on their expectations and requirements were well in line with the intended specifications of the ELSAH-patch system. However, certain technical aspects such as the lifetime, data security and accuracy require special attention during its development. In recent years, the development and application of wearables to monitor health and well-being has increased significantly in scientific as well as commercial settings. Driven by the growing functionality and affordability of miniaturized electronics, the widespread proliferation of smartphones and the growing consumer awareness of health and wellness, these wearables have rapidly become a prime example of electronic intelligent systems (ESS) with high market potential . AlreadyFor a comprehensive analysis of health, performance or stress levels, the measurement of physical parameters and vital signs is not sufficient. The continuous real-time detection of relevant human biomarkers using wearable chemical sensors enables more in-depth monitoring and medical diagnosis for the user . A biomaAlthough blood is generally considered the gold standard biofluid for diagnostics and analyses of biomarkers, the development of innovative wearable technologies has focused on non-invasive approaches because blood sampling is incompatible in personal  health care settings. Sweat, saliva or ocular fluid have been identified as alternative body fluids for biomarker analyses ,6,7,8.However, systems associated with the non-invasive sampling type face specific challenges ,9. ContaOne possible way out of these problems is to opt for minimally invasive measurement in the dermal interstitial fluid (ISF) instead. The dermal ISF can be accessed pain-free using minimally invasive microneedles  and is nThe EU-funded “electronic smart patch system for wireless monitoring of molecular biomarkers for health care and well-being” (ELSAH) project , which iSeveral devices are already on the market for the minimally invasive monitoring of glucose, for example, the FreeStyle Libre 2 system from Abbott Laboratories Ltd. or the Dexcom G6 system from Dexcom Inc. These devices only measure glucose (in the subcutaneous ISF), and applying the sensor might be painful. By contrast, the ELSAH-patch should provide a platform for multiplexed measurements of several biomarkers in real time, and its use should be pain-free.Since developers and possible end-users of the ELSAH-patch system may have different perspectives on the required specifications and demands, it is important to incorporate the target group’s expectations and requirements into the development process at an early stage to optimize the product for the market . For thiThe survey targeted potential end-users of the ELSAH-patch and intended to identify the expectations on and requirements for such a system. For this purpose, a questionnaire was developed which covered different aspects of the handling and use of the ELSAH-patch. The questionnaire was used as an online version on "surveymonkey.com". The paper-and-pencil method was used as an alternative. Data were collected over a period of 3 months from 06/2019 until 09/2019. To be included in the final data set, at least 80% of the questionnaire had to be completed.The participants had to be 18 years or older. No further exclusion criteria were defined, in order to achieve the highest possible number of responses. All subjects participated voluntarily without monetary incentive and provided written consent for inclusion in the study.The questionnaire consisted of 57 questions and was divided into six separate sections: (1) anthropometric/sociodemographic data and experience with glucose and lactate measurements, (2) an explanation of the ELSAH project, (3) user behavior and acceptance, (4) technical aspects and design, (5) software and data security and (6) pricing see . The parPrior to the survey, the questionnaire was reviewed by three scientific colleagues from different disciplines to ensure that the questions were understandable and unambiguous. Once their feedback had been incorporated, the questionnaire was distributed to individuals from the potential target groups to identify possible problems. This preliminary group included sports scientists, coaches and patients with diabetes mellitus (who often use continuous glucose-measuring systems), but also persons who were unfamiliar with sports and exercise and/or self-monitoring health variables to eliminate comprehension problems in relation to technical terms or expressions. The group’s feedback was used to adapt the questionnaire into its final version. The average time required to complete the questionnaire was 10–12 minutes.® 2016 for Windows .Before conducting the statistical analyses, the participants’ responses were corrected for input errors  and checked for plausibility. Implausible or inconsistent answers  were not considered in further analyses. The collected data were analyzed descriptively. Values are expressed as mean values ± standard deviations or as mean values and 95% confidence intervals (95%-CIs). Graphs were prepared using Microsoft Office ExcelThe ELSAH project was approved by the local Ethics Committee of the German Sport University Cologne . A total of 383 subjects participated in the survey. The responses of 316 subjects fulfilled the required 80% completeness, passed the plausibility check and were ultimately included for further analyses. Of the participants, 47.5% were female, 52.2% male and 0.3% diverse. The mean age of the population sample was 38.3 ± 14.5 years (min–max: 18–81 years). Over half of the sample (51.8%) had a higher education, and the monthly net income of 51.3% of the survey participants was between 1000 and 3000 EUR. About 20% earned less than 1000 EUR, and 20% more than 3000 EUR, while 7.7% did not report their monthly net income. 2 (min–max: 17.3–47.4 kg/m2). The participants spent an average of 5.8 ± 4.2 hours (min–max: 0–30 hours) per week on sports or exercise. The majority (75.3%) considered themselves recreational athletes, and 10.6% as elite athletes. The remaining 14.1% declared they did not engage in any physical activities.The mean body mass index (BMI) of the analyzed sample was 24.8 ± 4.5 kg/mAmong the subjects, 64 (20.4%) had some form of diabetes mellitus; 70.3% of them had diabetes mellitus type 1. The remaining persons had insulin-dependent (18.8%) or non-insulin-dependent (7.8%) type 2 diabetes mellitus or other forms of diabetes mellitus, such as gestational diabetes (3.1%).A total of 113 participants (35.8%) reported having experience with lactate measurements. The majority of them (87.9%) performed measurements less than once a month. Of the respondents, 62 (19.9%) stated that they had experience with glucose measurements. In contrast to lactate measurements, glucose measurements were generally performed more frequently among the subjects. Over three-quarters (77.4%) of them performed the measurements daily or several times a week; 14.5% performed them less than once a month. Moreover, 18.5% of the respondents said that they were experienced in using continuous glucose monitoring (CGM) systems.The participants stated a high general demand for a biochemical sensor system for molecular biomarkers such as the ELSAH-patch, while personal demand was also present but was slightly lower a. AccordRespondents who worked as doctors, sports scientists or trainers either “strongly agreed”  or “agreed”  that they would also apply the ELSAH-patch to others. A small percentage  “did not agree”, and 4.7% (95%-CI: 1.0–8.3%) “strongly disagreed” with this statement. The remaining 24.8% (95%-CI: 17.4–32.3%) were “neutral”.Independently of the price and field of application, 43.8% (95%-CI: 38.3–49.4%) of the participants would use the ELSAH-patch on an occasional (monthly) basis for lactate measurements. It would be used regularly (weekly) by 23.1% (95%-CI: 18.3–27.8%), and 11.0% (95%-CI: 7.5–14.5%) would even use it daily. By contrast, 14.0% (95-CI: 10.1–17.8%) claimed that they would only use it rarely (yearly) or saw absolutely no use in it . For glucose measurements, 23.9% (95%-CI: 19.2–28.7%) would use the ELSAH-patch permanently (daily), 21.4% (95%-CI: 16.8–25.9%) would use it regularly (weekly) and 32.0% (95%-CI: 26.8–37.2%) occasionally (monthly), while 14.2% (95%-CI: 10.3–18.1%) would rarely use the system (yearly) or not at all .Among the subjects, 61.1% (95%-CI: 54.9–67.4%) stated that the perceived pain during blood sampling for analysis using conventional systems did not prevent them from voluntarily performing glucose or lactate measurements. By contrast, the perceived pain did prevent 38.9% (95%-CI: 32.6–45.1%) of the participants from performing measurements, to a low extent , to some extent , to a great  or even to a very great extent .The majority of the participants “strongly agreed”  or “agreed”  that sustainability  would be a decisive criterion in their decision to buy the ELSAH-patch; 22.3% (95%-CI: 17.7–27.0%) were “neutral” about this question, while 8.7% (95%-CI: 5.6–11.9%) “disagreed” or even “strongly disagreed”  with this statement.Most participants would like to use the ELSAH-patch system in combination with their own mobile phone. The use of a PC or tablet was less popular by comparison, but the option to monitor the measurement values on another wearable  was preferred by more than every second person a. MultipThe respondents would prefer to wear the ELSAH-patch on their upper arm , where the patch should either be transparent  or match skin tone . The most suitable shapes according to the participants are round shapes such as oval, rectangular with rounded ends or circular b.The ELSAH-patch should be ready to use immediately  or at least within 30 minutes . During its operation, 22.6% (95%-CI: 18.0–27.2%) would prefer continuous monitoring (every minute), while 25.5% (95%-CI: 20.7–30.3%) would be satisfied with a 5-minute measuring interval. For 37.3% (95%-CI: 31.9–42.6%) of the participants, an interval of at least 15 minutes would also be sufficient. The length of the interval was “not relevant” for 14.6% of the participants (95%-CI: 10.7–18.6%).Without information about the planned operational lifetime of the ELSAH-patch, 29.1% (95%-CI: 24.0–34.1%) of the participants preferred a lifetime of up to 12 hours. For 27.5% (95%-CI: 22.5–32.4%), a lifetime of 24 hours would be sufficient. A lifetime of several days was favored by 25.6% (95%-CI: 20.7–30.4%), and 17.9% (95%-CI: 13.6–22.1%) stated that the ELSAH-patch should be operational for more than 1 week. Asked whether a 24-hour lifetime would be sufficient for their specific needs, 55.8% (95%-CI: 50.3–61.3%) agreed. For 73 of the participants , this life span would be insufficient. The remaining participants  neither agreed nor disagreed.Asked which other biomarkers would be of interest to the respondents and which should be measured by the ELSAH-patch (multiple answers possible), inflammatory markers , markers for myocardial infarction , hormones  and oncological factors/cancer markers  were selected from the listed markers. For the option to add unlisted markers, atherosclerotic markers, ketones and biomarkers for hydration were mentioned.In response to the question how the collected measurement values should be presented in the software (multiple answers possible), 75.7% (95%-CI: 70.9–80.5%) of participants preferred a comparison with previous measurement values or an assessment of whether the values are/are not critical to their health . A comparative visualization with data from a reference group was supported by 54.4% (95%-CI: 48.8–59.9%), and 50.5% (95%-CI: 44.9–56.1%) would like to have the possibility of inspecting the raw data.Participants were asked to rate potential functions and features that could be implemented in the ELSAH-patch software . InformaData security was also a very important factor for 69.8% (95%-CI: 64.8–74.9%) of the respondents and at least an important criterion for 17.8% (95%-CI: 13.6–22.0%). Only a minority of 2.5% (95%-CI: 0.8–4.3%) did not consider data security to be important. Accordingly, 52.1% (95%-CI: 46.5–57.6%) “strongly agreed” and 31.7% (95%-CI: 26.6–36.9%) “rather agreed” that a high level of data security  would influence their decision to buy the ELSAH-patch system. On the other hand, 86.1% (95%-CI: 82.3–89.9%) would also agree to allow specific persons  to access their data with their explicit consent.The participants were asked how much money they would be willing to spend per month on average for the complete ELSAH-patch system. Slightly over half of the respondents  would pay between 20 and 100 EUR per month, whereas 35.0% (95%-CI: 29.8–40.3%) would spend less than 20 EUR. Some respondents  would even be willing to spend 100–200 EUR, while none of the participants would spend more than 200 EUR. Other participants  would not buy the ELSAH-patch system at all.According to the survey results, the maximum price for a single ELSAH-patch, if the lifetime was 24 hours and the software was free of charge, should not exceed 10 EUR for 76.5% of the respondents (95%-CI: 71.8–81.2%); 12.7% (95%-CI: 9.0–16.4%) would pay a maximum price of between 10 and 15 EUR, and 4.4% (95%-CI: 2.2–6.7%) would even pay over 15 EUR. In this context, 6.3% of the participants (95%-CI: 3.7–9.0%) answered that they would not buy the ELSAH-patch system under the mentioned conditions.If a single ELSAH-patch would cost 15 EUR, the corresponding software/mobile app with all the previously defined specifications should not cost more than 5 EUR for 28.6% (95%-CI: 23.6–33.6%) of the participants. Around one-third  would be willing to spend between 5 and 15 EUR for the software. Another 30.8% (95%-CI: 25.7–35.9%) would even pay more than 15 EUR for the software, while 10.5% (95%-CI: 7.1–13.9%) would not pay for the software/mobile app under these conditions. ELSAH-patches should be waterproof/should not detach when sweating (even during high-intensity sports);ELSAH-patches should be easily available (short delivery time);Cost absorption by health insurance would be desirable in case of diseases ;There should be technical support/a hotline;The ELSAH-patch system should be easy to use (patch and software);Export options for data should be provided/data transfer to other platforms/apps should be possible.In response to the open-ended question what other factors would be important in relation to the ELSAH-patch, 39 participants suggested considering aspects such as:The survey results show high user acceptance for the ELSAH-patch system. The participants would prefer to use it for personal health care, but also identified possible applications within the field of physical activity/training. In general, the results show good congruence with the intended specifications of the ELSAH-patch on factors such as accuracy and data security, which should be implemented accordingly. The results of this study also provide important information for developers on aspects such as operational lifetime or water/sweat resistance, which should be taken into account.The high demand for such a system is in line with the immense interest in wearable devices for personal health care, fitness and well-being . The parMedical/well-being aspects, e.g., guidance on pathological limits or warnings for hypo-/hyperglycemic conditions, were more important for the respondents than support functions during physical activity/training. Therefore, high standards of accuracy and reliability are important. Measurement accuracy is essential, especially for low or rapidly changing glucose concentrations, and is still a major challenge for existing sensors . The firThe operating lifetime of the ELSAH-patch was planned to be 24 h. This would be sufficient for 55.8% of the respondents. However, especially for people with diabetes mellitus, continuous glucose monitoring over a long period of time is, of course, important for managing the disease. Therefore, a relatively high number of people with diabetes were among the 23.4% (95%-CI: 18.7–28.1%) of participants for whom a 24-hour lifetime would not be sufficient. The balancing act regarding users’ expectations and technical feasibility is a tremendous challenge for the ELSAH system developers. In a comparable survey on the general expectations for wearable and implantable sensors, 37% of the respondents stated that they expected a battery life of more than 6 months . Such exDaily life conditions are a further challenge for the ELSAH-patch. Preventing early sensor detachment is probably one of the most difficult tasks for developers. Accordingly, the participants mentioned this aspect in the open-ended question at the end of the questionnaire: the sensor should be waterproof and/or should not detach under conditions of sweating. Demands for the adhesion of the ELSAH-patch are high, especially when having a shower or swimming or during intensive physical activity (heavy sweating). The function of the ELSAH-patch system should not be restricted by these daily life conditions. In this context, it is important that the chosen adhesive ensures reliable operation without early detachment while avoiding skin irritations or allergic reactions already observed for other patch-based glucose-monitoring systems .Another very important issue for the ELSAH project will be ensuring data security. The potential end-users have high demands as regards the protection of their personal data. Since health-related information about glucose and lactate levels collected by the ELSAH-patch is highly sensitive, the misuse of data must be prevented. Self-perceived privacy control and trust have been identified as key factors for the intention to use health-related wearables in a former survey examining the decisions to use personal health record systems by young U.S. individuals . This isFor a complete profiling of a person’s well-being, a variety of parameters must be detected simultaneously. As the concept of the ELSAH-patch can easily be extended to the multiplexed detection of additional biomarkers, the participants were asked which other biomarkers would be of interest. Although the ELSAH project will initially focus on continuous measurement of glucose and lactate, it was important to obtain strategic information for the future market and developments. The results of the present survey/the end-users´ demands and expectations should be taken into account as far as possible in the development of the ELSAH-patch system. Users´ demands, for example, in terms of security, can be further addressed by encrypted end-to-end data transmission from the ELSAH-patch to the terminal device and encrypted data storage. User authentication and "privacy by design" and "privacy by default" principles should guarantee a high level of privacy and security. Furthermore, the users´ expectations in terms of tracking several other molecules/biomarkers could also be fulfilled. The concept of the ELSAH-patch allows adding additional electrodes with specific enzymes for the quantification of further biomarkers. After evaluating the possibilities of the production companies, the respondents´ wishes, for example, with regard to the shape and color of the patches, should also be considered.The present study sample is not representative in relation to Germany’s total population. In a representative survey on health and physical activity in Germany with 2885 participants, at least half of the respondents stated that they were not physically active in their leisure time . In this study, non-active persons  represented only a small proportion of the sample. Although the analyzed sample in this study is different from the total population, it can be assumed that the ELSAH-patch target group could have comparable characteristics, as the ELSAH project primarily targets personal health care, fitness and well-being, and the majority of the potential end-users are expected to be very health-conscious.The intended specifications of the ELSAH-patch correspond well with the results of the survey on the expectations and requirements of possible end-users. The findings confirm the high relevance of a minimally invasive smart patch system for the wireless monitoring of molecular biomarkers and indicate high user acceptance for its use in health care, fitness and well-being applications. Over half of the respondents would pay between 20 and 100 EUR per month for such a system. The study’s results emphasize the importance of the ambitious standards for accuracy and data security and their consequent implementation. In addition, important information on operational lifetime and water/sweat resistance was obtained, which should be taken into account in the development process.