We assessed symptoms and complications, incidence/management of vaso‐occlusive crises (VOCs), treatment utilization/satisfaction, and the impact of SCD on education/employment. Certain symptoms  and complications  were reported proportionally more by patients in the USA than in the HI/LMI countries. Self‐reported VOCs were more common (mean [SD]: 7.1 [5.7] vs. 5.5 [8.9] and 4.4 [4.6] in the previous 12 months) and were managed more often by hospitalization (52% vs. 24% and 32%) in the USA than the HI and LMI countries. A higher proportion of patients from the USA than the HI/LMI countries reported a negative impact of SCD on their employment/schooling. Although high overall satisfaction with current treatments was reported globally, most patients indicated a strong desire for alternative pain medications. There are likely several reasons for the relatively high patient‐reported burden in the USA group compared with the HI/LMI countries, including an older population and differences in newborn screening programs and pediatric/adult transition of care. It is clear that there is an urgent need for improved understanding and management of SCD globally, not just in the USA.The international Sickle Cell World Assessment Survey (SWAY) reported a high impact of sickle cell disease (SCD) on patients' daily lives globally. In this study, we analyzed whether the reported burden differed between patients from the USA ( Therefore, the exact global prevalence of SCD is unknown.The international Sickle Cell World Assessment Survey (SWAY) was a cross‐sectional questionnaire that aimed to better inform the management and treatment of SCD, and support global healthcare policy and delivery, by collecting real‐world insights into the impact of SCD on patients' daily lives and the treatment they receive.The primary analysis of SWAY demonstrated that the unmet needs in SCD care and management differ substantially between HI and LMI countries.22.1Full methodological details have been described previously.2.1.1Briefly, SWAY was a multi‐country, cross‐sectional survey conducted in 16 countries Figure  between 2.1.2Patients aged ≥6 years with a diagnosis of SCD participated in SWAY. Patients were recruited either by treating HCPs during routine consultations or via invitation from PAGs. A proxy (parent/guardian/caregiver) completed the survey for patients aged 6–11 years. Patients aged ≥12 years could complete the survey independently or seek input from a parent/guardian/caregiver, or a proxy could complete the survey for them. HCPs were also invited to take a separate survey, but only results from the patient survey are presented here.2.1.3Collected data included: patient demographics, SCD symptoms , complications , incidence and management of VOCs, medications received for SCD (currently and ever), and satisfaction with these medications. The survey was completed prior to the approval of crizanlizumab (approved by the US Food and Drug Administration [FDA] in 2019 and European Medicines Agency in 2020) and voxelotor (approved by the FDA in 2019); therefore, these treatments were not included in the survey. Question format was predominantly multiple choice or ratings based. For ratings‐based questions, participants recorded their agreement with a given statement using a 7‐point Likert scale. The scale was defined for each question . A score of 5, 6, or 7 was deemed to indicate “high impact,” “high severity,” “high satisfaction,” or “strong agreement,” respectively.2.2All reported data and associated analyses are descriptive. All data comparisons are between the USA and other countries participating in SWAY, stratified according to economic status (HI or LMI). The World Bank definition for an HI economy 33.1A total of 2145 patients participated in SWAY, comprising 384 (18%) from the USA, 820 (38%) from other HI countries , and 941 (44%) from LMI countries  Figure , Table 1Demographics and baseline characteristics were generally similar between the USA and HI groups, with more apparent differences between the USA and LMI groups Table . Importa3.2Self‐reported symptoms experienced in the month prior to survey completion were generally consistent across groups. Anxiety, bone aches, breathing issues, fatigue, joint stiffness, headache, low mood, and yellow eyes were all in the top 10 most common symptoms in each group, and fatigue (50%–79%) and bone aches (43%–66%) were both in the top three Figure . AlthougSimilarly, nine of the ten most frequently self‐reported complications were the same in each group . Joint issues (44%–67%) and fever (58%–69%) were both in the top three most‐common complications in each group Figure . Several3.3The self‐reported VOC burden was higher in the USA group than in the HI and LMI groups; the mean [standard deviation (SD)] number of VOCs in the 12 months prior to survey completion was 7.1 (5.7) versus 5.5 (8.9) and 4.4 (4.6), respectively. During the same period, the mean (SD) number of VOCs reported in pediatric patients (≤18 years) was 4.3 (3.0) versus 5.5 (8.9) and 4.4 (4.5) in the USA, HI, and LMI groups, respectively. In adult patients (>18 years), the mean [SD] number of VOCs was higher in the USA (7.9 [6.0]) than the HI (5.4 [8.9]) and LMI (4.3 [4.6]) groups. Corresponding median values for VOC burden can be found in Table The most frequently reported management of VOCs was overnight in hospital for both the USA and LMI groups , whereas VOCs were most often managed at home in the HI group (31%). The proportion of VOCs managed in the community  was lower in the USA group than in the HI group, while the proportion managed overnight in hospital was higher in the USA group than in either the HI or LMI groups. Compared with the LMI group, the proportion of both VOCs managed in the community or in the ED was lower in the USA group Figure .The most common reasons for managing VOCs at home were consistent across the USA, HI, and LMI groups, with poor prior experience at the ED/hospital  and the belief that medical assistance was not required  being two of the top three reasons in each group. The most common methods for managing VOCs at home were resting and/or sleeping  and drinking plenty of fluids . Taking opioid painkillers was reported by 73% and 66% of patients in the USA and HI groups, respectively, compared with only 34% in the LMI group.3.4At the time of the survey, a higher proportion from the USA group than both the HI and LMI groups reported current opioid use  Figure . In cont3.5I would recommend my SCD treatment to another SCD patient” (66% vs. 53%) and “I do not want to take my SCD treatment for the foreseeable future”  and LMI  groups, but higher in the HI group . A higher proportion of patients from the USA group reported not working, being on disability, or being on long‐term sick leave  than in the HI  and LMI  groups. For seven of the nine statements, a higher proportion of patients from the USA group than both the HI and LMI groups reported that SCD had had a negative impact on work life  were similar in the USA  by USA patients was fever (vs. LMI patients only). This may be related to public health measures in the USA that have helped to reduce infection, such as penicillin prophylaxis and nationwide vaccination programs. However, it is likely that the higher symptom/complication burden is not reflective of more severe disease in the USA than in HI and LMI countries, but instead relates to various factors. For example, availability and access to healthcare are influenced, in part, by the wealth of a country and the relative allocation of resources to healthcare. Therefore, it is interesting to note that according to the World Bank, the gross domestic product (GDP) for the USA is approximately 15 times greater than the average GDP of the other HI countries in SWAY .There are likely several reasons for the reported higher VOC burden in the USA group than in both the HI and LMI groups. The US campaign to identify pain as the “fifth vital sign”Not only was the VOC burden in the USA group higher than in HI and LMI countries , it was substantially higher than reported in previous studies.n = 232; aged 16–64 years), 10.6%–19.8% of reported crises were cared for in the hospital setting, implying that a large proportion were managed at home .The proportion of VOCs that patients reported as requiring overnight hospital stays in the USA group was approximately twice that of both the HI and LMI groups . Various factors could contribute to the reliance on hospital treatment in the USA, including a healthcare system that is heavily centered around ED/hospital care, combined with insurance‐based healthcare and the existing liability culture, as well as easy access to hospital care and the potential lack of providers who feel comfortable treating pain in the community. The dependence on hospitals for managing VOCs suggests that SCD carries a higher societal burden and has a greater impact on healthcare resource utilization in the USA than in other HI and LMI countries. Around one‐fifth (22%) of VOCs experienced in the USA were managed at home according to patient reports, which is a lower rate than observed in other studies. In the PiSCES study (Reported current use of opioids was particularly high among patients in the USA group (63%) compared with the HI (44%) and LMI (13%) groups. This finding was reflected in two recent studies: one that reported that 240 million opioid prescriptions were dispensed in the USA in 2015 Overall levels of treatment satisfaction were similar between the USA group and the HI and LMI groups. It seems contradictory that patients in the USA, who reported a high VOC burden, also express a comparatively high level of satisfaction with their treatment's control of their SCD. This paradox is also reflected in patients who received opioid‐based and HU‐based regimens Figure . Most paA consistently higher proportion of patients from the USA than from other HI and LMI countries reported a high impact of SCD on their education .5Data presented here further support our previous finding that the burden of SCD on patients' lives is substantial regardless of geographical location.All authors  were members of the SWAY steering committee, of which Ifeyinwa Osunkwo and John James were co‐chairs. All authors contributed to the survey design and data interpretation, and reviewed and approved the report. John James and Cassandra Trimnell contributed to patient recruitment.Novartis provided sponsorship and was involved in running the survey. Adelphi Real World (ARW) designed the survey in collaboration with the SWAY steering committee and Novartis. Funding was provided by Novartis Pharmaceuticals Corporation to ARW for the survey design, data collection, and data analysis, and to Mudskipper Business Ltd, Bollington, Macclesfield, UK for medical writing support.Hematology News. J.J. reports employment by the Sickle Cell Society and honoraria from Novartis. F.E.‐R. reports research funding from Cyclerion, Novartis, and Pfizer; and advisory board participation for Novartis, Global Blood Therapeutics, and bluebird bio. A.N. reports consultancy/expert testimony for bluebird bio, Global Blood Therapeutics, and Novartis. C.P.M. reports consultancy for Agios, bluebird bio, Emmaus, Forma Therapeutics, Global Blood Therapeutics, Novartis, Roche, and Sanguine. C.T. reports consultancy/expert testimony for Novartis, Cyclerion, and Global Blood Therapeutics. J.P. is an employee of Novartis Pharmaceuticals Corporation. N.R. is an employee of Novartis Pharma AG. O.R.‐H. and T.B. are employees of Adelphi Real World, which received payment from Novartis Pharmaceuticals as part of this research. B.A. reports consultancy or membership on an advisory committee for Agios, Aruvant, bluebird bio, CRISPR/Vertex, Cyclerion, Emmaus, Forma Therapeutics, Global Blood Therapeutics, Hemanext, Novartis, Novo Nordisk, Sanofi Genzyme, and Terumo BCT; and research funding from Forma Therapeutics, Global Blood Therapeutics, Hemanext, Imara, and Novartis.I.O. reports consultancy for Agios, Cheisi, Cyclerion, FORMA Therapeutics, Global Blood Therapeutics, HCP Live, Novartis, and Takeda; speakers' bureau for Emmaus, Global Blood Therapeutics, and Novartis; advisory board for Acceleron, Cyclerion, Cheisi, Emmaus, FORMA therapeutics, Global Blood Therapeutics, Novartis, and Novo‐Nordisk; grants from Centers for Disease Control (CDC), Department for Public Health (DPH), Health Resources and Services Administration (HRSA), Patient Centered Outcomes Research Institute (PCORI), and NC; Data and Safety Monitoring Board (DSMB) membership for Micella Biopharma; and Editor‐In‐Chief for Appendix S1Click here for additional data file.


The adopted strategy involved replacing the 4-fluorophenyl tail in SLC-0111 with a benzothiazole motif that attached to the ureido linker to produce compounds 8c and its regioisomers 8a-b. In addition, the ureido spacer was elongated by methylene or ethylene groups to afford the counterparts 10 and 12. In turn, the primary sulfamoyl zinc binding group (ZBG) was either substituted or replaced by carboxylic acid functionality in order to provide the secondary sulphonamide-based SLC-0111 analogues 16a-b, and the carboxylic acid derivatives 14a-c, respectively. All compounds  were tested for their ability to inhibit CA isoforms CA I, II, IX and XII. Additionally, the in vitro anticancer properties of the developed CAIs were evaluated.In this work, different series of benzothiazole-based sulphonamides  Strikingly, tail approach stood out as the most successful and effective tool to improve the potency and selectivity of sulphonamide-based carbonic anhydrase inhibitors (CAIs),Interestingly, the trans-membranal hCA IX inhibitor which, for the management of metastatic hypoxic solid tumours, is currently being investigated within phase I/II clinical trials,,hCA IX exploiting bioisosteric replacement approach via replacement of the SLC-0111aryl tail by various sets of chemical scaffolds . All coupling constant (J) values are reported in hertz. Both ethyl 1,3-benzothiazole-2-carboxylate 3 and benzo[d]thiazole-2-carbohydrazide 4 were prepared as previously reportedUncorrected melting points were measured using a Stuart melting point device. In addition, the Schimadzu FT-IR 8400S spectrophotometer was used to record the IR spectra, whereas the Bruker spectrophotometer (400 MHz) was used to record the NMR spectra. White crystals, m.p. = 69–72 °C (reported m.p. = 68–69 °C)White crystals, m.p. = 174–175 °C (reported m.p. = 173–174 °C)d]thiazole-2-carbohydrazide 4  and sodium nitrite  in glacial acetic acid was stirred in an ice bath for 2 h. Azide 4 was produced by air-drying the generated solid, washing it with water (3 × 4 mL), and collecting it using filtration. Azide 4 was then heated for 30 min at reflux in dry xylene. To the prepared xylene solution, the appropriate amine derivative benzenesulfonamide 9, 4–(2-aminoethyl)benzenesulfonamide 11, aminobenzoic acids 13a-c, and secondary sulphonamides 15a-b) was added. After being refluxed for four hours, the reaction mixture was allowed to settle down to room temperature. The desired benzothiazole sulphonamides and carboxylic acids were obtained by filtering, washing the formed precipitate with methylene chloride (3 × 3 mL), drying it, and recrystallizing it from isopropyl alcohol.A mixture of benzo[8a-c, 10, 12, and 16a-b) and carboxylic acids (14a-c) were described in the Supplementary Materials.Both spectral (NMR and IR) and elemental analysis for the newly prepared sulphonamides benzenesulfonamide 9 and 4–(2-aminoethyl)benzenesulfonamide 11 in refluxing xylene to yield target benzothiazole-derived sulphonamides 10 and 12, respectively  was adopted as a controlI) manifested in The herein synthesised benzothiazole-derived sulphonamides 8a-c, 10, 12, 16a-b and the carboxylic acids 14a-c displayed diverse off-target hCA I inhibition profile spanning from nanomolar to high micromolar inhibitory constants (KIs = 61.5 nM to > 100 µM), 8a-c, they exerted low to moderate inhibitory activities towards the dominant hCA I with KIs ranged from 361.7 nM to 12.59 µM. Noteworthy, the switching of sulphonamide anchoring moiety from ortho- and meta positions  to para position potentially elevated the inhibition constant to the nanomolar level . Notably, the elongation of the ureido spacer in the p-benzenesulfonamide counterpart 8c (KI = 361.7 nM) by one carbon sharply reduced hCA I inhibitory potency , whereas its elongation by two carbons led to sensible enhancement in hCA I inhibitory impact providing the most potent hCA I inhibitor within the current study . In contrast, the bioisosteric replacement of the sulphonamide zinc binding functionality in 8a-c by carboxylic acid moiety 14a-c dramatically diminished hCA I inhibition constants to high micromolar values . Furthermore, it was noted that the inclusion of secondary sulfamoyl functionality totally abolished hCA I inhibitory effect  compared to the primary sulfamoyl-appended sulphonamides 8a-c.The herein tested benzothiazole-based sulphonamides in vitro kinetic data towards the physiologically relevant hCA II isoform presented inhibition pattern similar to hCA I, 8a-c exhibited moderate to high hCA II inhibitory potential with KIs spanning between 54.1 and 785.2 nM. While the incorporation of ortho or meta sulphonamide demonstrated moderate hCA II inhibition , the shifting of this sulfamoyl to para position interestingly improved hCA II inhibition constant to two-digits value . To explore the impact of linker length, the obtained results revealed that elongation of the ureido linker in 8c (KI = 54.1 nm) by one carbon significantly decreased the inhibitory action against hCA II by 4-fold , whereas the elongation of this linker by two carbons was more advantageous furnishing the most powerful hCA II inhibitor within this series (KI = 28.5 nM) in a similar way to the hCA I inhibition profile. Similarly, the appending of carboxyl group as a zinc anchoring moiety 14a-c in place of the sulfamoyl functionality 8a-c (KIs range 54.1– 785.2 nM) drastically declined hCA II inhibition to micromolar level . In addition, the applying of secondary sulfamoyl group 16a-b completely abolished hCA II inhibitory power similar to hCA I inhibition data.Interestingly, the hCA IX isozyme  to para position 8c enhanced the hCA IX inhibitory power , while the elongation of ureido linker in 8c by one carbon decreased the inhibition potency by the half . On the other hand, extending such a linker by two carbons resulted in the production of the most efficient hCA IX inhibitor within the scope of the present study . Additionally, the replacement of the sulfamoyl zinc binding group in 8a-c (KI range 31.5 to 65.3 nM) by carboxylic acid functionality sharply lowered the hCA IX inhibition constants . Like the hCA I and II inhibition outcomes, the incorporation of 3,5-dimethyl-1,2-oxazole-bearing secondary sulphonamide entirely revoked the hCA IX inhibitory efficiency , whereas the inclusion of thiazole-appended secondary sulphonamide 16a resulted in very weak hCA IX inhibition (KI of 56.09 µM).Concerning the inhibitory influence of the here evaluated benzothiazole-based SLC-0111 analogues towards cancer-associated  isozyme , the prihCA XII isoform, the herein assessed benzothiazole-derived SLC-0111 analogues demonstrated diverse potencies in a similar behaviour as hCA I, II and IX isoforms as depicted in 8a-c, 10 and 12 showed the most favourable inhibition profile against hCA XII isoform demonstrating inhibition constants KIs ranged from 29.3 to 57.5 nM. For the ureido linker-grafted sulphonamides 8a-c, the para regioisomer 8c was the most potent hCA XII inhibitor with KI = 29.3 nM, similarly the ortho and meta regioisomers exhibited potential hCA XII inhibition . Moreover, the elongation of the ureido linker in 8c (KI = 29.3 nM) by one or two carbons slightly reduced the inhibition constants . As obtained from hCA I, II and IX inhibitory investigations, the bioisosteric replacement of the sulphonamide functionality in 8a-c (KIs range 29.3 − 57.5 nM) with carboxylic acid group dramatically decreased the hCA XII inhibitory effect . Furthermore, it was noted that the inclusion of secondary sulfamoyl functionality 16a-b markedly declined hCA XII inhibition data, while the grafting of thiazole-bearing sulfamoyl 16a resulted in KI = 32.5 µM, the introduction of 3,5-dimethyl-1,2-oxazole-bearing secondary sulphonamide 16b completely abolished the hCA XII inhibition (KI > 100 µM).In the context of inhibitory activities towards the second tumour-related para primary sulfamoyl functionality in conjunction with the elongation of its ureido linker by two carbons furnished the most potent inhibitors towards the tumour-related hCA IX with inhibition constants better than the lead SLC-0111 . Undesirably such improvement in hCA IX inhibition for the promising candidates (8c and 12) was concomitant with the enhancement in inhibition of the ubiquitous hCA I  and II isoforms (IX/II S.I. = 1.7 for both) compared to SLC-0111 . Consequently, the resulting potent benzothiazole-tethered SLC-0111 analogues 8c and 12 can be employed as leads for further optimisation to develop promising candidates with superior potency and selectivity towards the cancer-associated isozymes over the physiologically dominant hCA I and II isoforms.Collectively, the elicited SAR hinted out that the replacement of 4-fluorophenyl tail in SLC-0111 with benzothiazole motif while maintaining the 8a-c, 10, 12, 16a-b and the carboxylic acids 14a-c were explored for their potential antitumor activities at the National Cancer Institute (NCI-USA) within the Developmental Therapeutic Program, utilising the US-NCI protocol and the sulforhodamine B (SRB) colorimetric assay for cell growth and viability evaluation,,,All herein developed benzothiazole-derived sulphonamides 8b. Sulphonamide 8b displayed selective anti-proliferative activity (GI > 30%) towards twenty cancer cell lines belonging to all tumour subpanels, except the prostate cancer subpanel, with GI% range of 31–54% (8b (GI = 54%) was observed for the breast T-47D cancer cell line. 8b.The obtained results revealed that the examined molecules have weak or non-significant antitumor activities towards most NCI cancer cell lines, except f 31–54% . The bes8c exerted cell growth inhibition (GI) equals about 20% towards non-small cell lung cancer (EKVX) and breast cancer (MCF7 and T-47D) cell lines, as well as GI = 24% towards renal cancer (UO-31) cell line. Sulphonamide 10 displayed GI equals about 20% against non-small cell lung cancer (NCI-H226 and EKVX), and breast cancer (MCF7 and T-47D) cell lines, in addition, it exerted about 25% GI towards ovarian cancer (IGROV1) and CNS cancer (SNB-75) cell lines. Superiorly, the renal cancer (UO-31) cell line was the most sensitive one to the effect of sulphonamide 10 with a GI value of 33%. Moreover, non-small cell lung cancer (EKVX), ovarian cancer (IGROV1) and CNS cancer (SNB-75), and renal cancer (UO-31) and breast cancer (MCF7 and T-47D) cell lines were the most susceptible cells to the impact of sulphonamides 16a and 16b with GI % = 27, 28, 29, 37, 24, 22 for 16a, and GI % = 19, 24, 37, 29, 24, 16 for 16b.Sulphonamide 14, carboxylic acid derivative 14a was found to possess a moderate growth inhibitory effect against non-small cell lung cancer (EKVX), ovarian cancer (IGROV1), CNS cancer (SNB-75), and renal cancer (CAKI-1 and UO-31) cell lines with inhibition % 22, 27, 20, 20, and 32, respectively. Also, carboxylic acid derivative 14b displayed GI more than 20% against ovarian cancer (IGROV1), CNS cancer (SNB-75), and renal cancer (UO-31) cell lines, whereas compound 14c exerted GI more than 20% against ovarian cancer (IGROV1), non-small cell lung cancer (EKVX), renal cancer (UO-31) and breast cancer (MCF7 and T-47D) cell lines.Regarding the anticancer activities of series 8b elicited an excellent selectivity towards hCA IX and XII over the off-target hCA I, with selective indexes (SIs) equal 82.6 and 70.2, respectively. In addition, only sulphonamide 8b demonstrated excellent selectivity towards hCA IX and XII in comparison to hCA II, with SI values of 13.3 and 11.3, respectively. As a consequence of this, sulphonamide 8b maintained both its activity and its selectivity with regard to the hCA IX and XII isoforms that are associated with cancer. In addition, according to the findings of the US-NCI assay that was discussed before, sulphonamide 8b was determined to be the most effective anticancer molecules herein reported. As a consequence, sulphonamide 8b was evaluated for its anticancer effect towards breast cancer (T-47D and MCF-7) cell lines within the hypoxic conditions, using the SRB assay. The assay results that presented in 8b had good IC50 values (6.73 ± 0.28 and 9.16 ± 0.70) against T-47D and MCF-7 cells, respectively.The inhibition constants presented in 8a-c, 10, 12, 16a-b and carboxylic acids as novel SLC-0111 analogues, and assessed their CA inhibitory effects towards CA I, II, IX and XII isoforms. Different drug design approaches were utilised. The benzothiazole motif was appended to the ureido linker instead of the SLC-0111 fluorophenyl tail to produce compounds 8c and its regioisomers 8a-b. In addition, the ureido spacer was elongated by methylene or ethylene groups to afford the counterparts 10 and 12. In turn, the functionality of the primary ZBG was either replaced by carboxylic acid or it was substituted in order to produce the carboxylic acid derivatives 14a-c and the secondary sulphonamide-based SLC-0111 analogues 16a-b, respectively. The elicited SAR, from this study, hinted out that the introduction of para primary sulfamoyl functionality along with elongation of the ureido linker by two carbons were more beneficial for the cancer-related hCA IX and XII inhibition. The primary sulfamoyl-bearing analogues 8a-c, 10 and 12 disclosed the most favourable inhibition profile against tumour-related hCA IX and XII isoforms demonstrating inhibition constants ranged from 16.4 to 65.3 nM and from 29.3 to 57.5 nM, respectively. Moreover, all herein developed benzothiazole-derived sulphonamides 8a-c, 10, 12, 16a-b and the carboxylic acids 14a-c were explored for their potential antitumor activities at the NCI-National Cancer Institute. The examined molecules have weak or non-significant antitumor activities towards most NCI cancer cell lines, except sulphonamide 8b which displayed selective anti-proliferative activity (GI > 30%) towards twenty cancer cell lines belonging to all tumour subpanels, except the prostate cancer subpanel. It is interesting to mention that 8b elicited an excellent selectivity towards hCA IX and XII over the off-target hCA I, with selective indexes equal to 82.6 and 70.2, respectively. Additionally, it demonstrated good selectivity towards hCA IX and XII over hCA II with selective indexes of 13.3 and 11.3, respectively. Furthermore, the cytotoxicity SRB assay showed that sulphonamide 8b had good IC50 values (6.73 ± 0.28 and 9.16 ± 0.70) against breast cancer T-47D and MCF-7 cells, respectively.This study developed different series of benzothiazole-based sulphonamides Click here for additional data file.


Preterm birth (PTB) is one of the leading causes of deaths in infants under the age of five. Known risk factors of PTB include genetic factors, lifestyle choices or infection. Identification of omic biomarkers associated with PTB could aid clinical management of women at high risk of early labour and thereby reduce neonatal morbidity. This systematic literature review aimed to identify and summarise maternal omic and multi-omic  biomarker studies of PTB. Original research articles were retrieved from three databases: PubMed, Web of Science and Science Direct, using specified search terms for each omic discipline. PTB studies investigating genomics, transcriptomics, proteomics or metabolomics biomarkers prior to onset of labour were included. Data were collected and reviewed independently. Pathway analyses were completed on the biomarkers from non-targeted omic studies using Reactome pathway analysis tool. A total of 149 omic studies were identified; most of the literature investigated proteomic biomarkers. Pathway analysis identified several cellular processes associated with the omic biomarkers reported in the literature. Study heterogeneity was observed across the research articles, including the use of different gestation cut-offs to define PTB. Infection/inflammatory biomarkers were identified across majority of papers using a range of targeted and non-targeted approaches. Preterm birth (PTB), defined by the World Health Organisation (WHO) as birth less than 37 weeks of gestation, is a complex multi-factorial condition with no robust biomarkers. A higher rate of morbidity in neonates is associated with ‘very preterm’ births (between 28 and 32 weeks of gestation) compared with ‘moderate to late preterm’ births (32 to 37 weeks of gestation) Refs , 2. Non-et al.  Ref. . Studiesal. Ref.  reportedal. Ref. .A more personalised approach of screening women at risk of PTB is required to improve pregnancy outcomes, and hence reduce rates of PTB, as opposed to the traditional methods that are currently used (such as collecting obstetric history or ultrasound scans) Ref. . In the EBF1 (early B-cell factor 1), and various signalling molecules, for instance Wnt, have been indicated as potential biomarkers of PTB in the literature  reported by Heng et al.  using microarray or sequencing technology have highlighted more candidate biomarkers including al. Ref. –18. miRNal. Ref. . Gene exal. Ref. –22.Metabolites are small molecules that are part of primary and intermediate metabolism that can help unveil the underlying pathophysiology of early labour Refs , 24. MasDifferent approaches have been implemented for omic studies such as targeted and non-targeted (or unbiased) techniques. Unbiased methods have enhanced exploration of the genome, transcriptome, proteome and metabolome enabling detection of candidate biomarkers related to a disease Refs , 15, 24.The pathways involved with the onset of sPTB are not yet known, even though several omic studies have suggested different markers of PTB (or sPTB or PPROM). Multi-omic data analysis approaches could assist with (1) identification of the mechanistic pathways initiated in PTB, by exploring interactions between different types of omic data; (2) improve our understanding of the ‘systems biology’ of PTB and (3) determine biomarkers in early stages of pregnancy for earlier and more effective clinical intervention to improve pregnancy outcome and neonatal health outcome. A summary of candidate omic biomarkers could aid future PTB omic studies, particularly multi-omic research. This systematic literature review aimed to (1) identify and summarise maternal omic  biomarker studies of PTB, including the phenotypes sPTB and PPROM and (2) of these studies, identify which studies performed multi-omic research.Genomics: ((Preterm birth OR preterm labour OR preterm delivery OR pregnancy OR premature birth OR premature labour OR premature delivery)) AND  AND (genomics OR genetics OR genome wide association OR GWAS OR genetic associations OR DNA OR single nucleotide polymorphisms OR epigenetic OR epigenome OR methylation).Transcriptomics: ((Preterm birth OR preterm labour OR preterm delivery OR pregnancy OR premature birth OR premature labour OR premature delivery)) AND  AND (transcriptomics OR RNA OR mRNA OR miRNA OR microRNA OR gene expression profiling OR RNA profiling OR microRNA profiling OR transcriptome).Proteomics: ((Preterm birth OR preterm labour OR preterm delivery OR pregnancy OR premature birth OR premature labour OR premature delivery)) AND  AND .Metabolomics: ((Preterm birth OR preterm labour OR preterm delivery OR pregnancy OR premature birth OR premature labour OR premature delivery)) AND  AND (metabolomics OR metabolites OR metabolome).Literature searches were conducted using three databases: PubMed, Web of Science and Science Direct. The resulting literature studies were filtered for journal (research) articles and human studies only. Original research articles from individual omic fields, published up to and including November 2020, were identified using the following search terms:Literature was screened and selected if the following inclusion criteria were met: an original research article investigating PTB ; maternal sample (human only) was analysed ; the sample was taken before start of labour process or symptoms and was a biomarker study with omic methods or analysis were indicated. Research of both foetal and maternal samples was included but only maternal analysis results were reported in this review .Studies were excluded if samples were collected after patients were admitted to hospital because of presenting symptoms of PTB (such as start of contractions or ruptured membranes observed) or if the births were iatrogenic . Genetic studies investigating familial relative inheritability of genes associated with PTB were excluded as no direct comparisons between term and PTB outcomes based on maternal genes.Papers that reported investigation of more than one omic dataset were allocated to one omic systematic search to avoid duplication.Research articles that met the review criteria were summarised into targeted studies (where a select number of candidate markers was chosen for exploration) or non-targeted investigations  based on reported methods and technologies applied.Biomarkers reported in the literature from non-targeted approaches were collated per omic field . Duplicates were removed and each omic list was uploaded to Reactome for pathway analyses Refs , 28. Litn = 79), followed by genomics (n = 39), metabolomics (n = 20) and transcriptomics research (n = 11).PRISMA diagrams of the individual omic systematic searches are summarised in Of the 39 genomic studies identified, nine applied non-targeted approaches (including microarrays) , whereasEBF1 and NFKB1 (nuclear factor kappa B subunit 1), both of which are inflammation-related  across different ethnicities were identified as associated with PTB or sPTB . In Euroted Refs , 30  (rs2277698), COL4A3  (rs1882435) and TNF variants were explored in more than one targeted study (Table S1). Frey et al.  rs77698, COet al.  was associated with an increased risk of PPROM. Toll-like receptors are proinflammatory agonists, gene variants of which were associated with an increased risk of PPROM as reported by Ramos et al. . Comparison of these studies highlighted 29 weeks of gestation as the lowest time point applied, whereas the highest and most common was 37 weeks of gestation threshold .n = 14), miRNA names (n = 35), UniProt ID for proteins (n = 158) and KEGG IDs for metabolites (n = 60) were retrieved from the respective non-targeted omic studies and included in the pathway analyses. In total, 24 pathways were detected for genomics, 4 for transcriptomics, 102 for proteomics and 72 metabolomics, at P < 0.05. After correction for multiple testing (FDR P < 0.05), the number of significant pathways reduced to 2 for transcriptomics, 44 for proteomics and 19 for metabolomic markers. No pathways were significant for genomics biomarkers at FDR P < 0.05. Top pathways for each omic discipline are summarised in Table S5.Gene symbols (P < 0.05) (Table S5). Other identified proteomic biomarkers such as pregnancy associated plasma protein A (PAPPA) were also mapped to this pathway, indicating the role of PAPPA in regulating insulin-like growth factor.Multiple insulin-like growth factor-binding proteins and ILs identified from the literature were indicated in the significant insulin-like growth factor-binding pathway (FDR P < 0.05) was obtained from the metabolomics biomarkers reported in PTB literature. This pathway matched with several input metabolites including acetate, creatinine and histidine.Solute-carrier transporter pathway  (Table S5), in which ATP-binding cassette subfamily A type 1 (ABCA1) and G type 1 (ABCG1) were found.Non-targeted transcriptomics pathway over-representation analysis highlighted cholesterol transport regulation pathway (FDR CALCR) and WNT4. These were related to female reproductive system development and WNT4 was identified as a potential PTB biomarker by Zhang et al.  were identified across genomics, transcriptomics, proteomics and metabolomics. Infection pathway-related molecules, for example IL-6, TNF, TLR4 and prostaglandins were commonly reported across these studies. Cytokines have been suggested to play a key role in PTB . This overlapped with the other omic results, particularly for protein levels of TNF and ILs . To date, no online platforms can implement pathway analysis of all four omic disciplines  using the molecule identifiers selected in this review, thereby, reducing the capability of investigating the interaction between the omic layers.Pathway analysis of non-targeted individual omic layers indicated cellular processes associated with infection-related functions. Few pathways were significant at FDR Meta-analysis including all the studies in this review could not be performed because of heterogeneity caused by differences in factors including technology or methods, study design, sampling time and PTB outcome definition. Samples were obtained from first trimester up to a few days before the patient delivered or started experiencing contractions prior to or around third trimester. Furthermore, different gestational cut-offs were applied across the studies . Different ethnic populations were included in the genomics studies, which would cause genetic heterogeneity if meta-analyses were to be performed. Targeted and non-targeted studies could not be combined as this would lead to bias in interpretation and therefore, meta-analysis was not suitable for this review.et al. , though this is considered late-PTB by the definition provided by the WHO and thereby more likely to detect molecular changes closer to term delivery. Fewer studies applied earlier gestational age thresholds; the earliest was 29 weeks as reported by Annells al. Ref. . Each stal. Ref.  or plasmal. Ref. . These shttps://www.marchofdimes.org/index.aspx), who have funded several international PTB research centres that are leading global multi-centre PTB omic research. Large cohort studies, with a robust study design, can enable firm conclusions to be drawn.Current PTB prevention guidelines in the UK recommend that women experiencing PTB symptoms at ≤34 weeks of gestation are in most need of PTB prevention treatment, therefore a diagnostic screen before this timepoint would be appropriate Ref. . An ideaThe studies outlined in this review implemented different experimental approaches and study designs for biomarker identification, but these were not validated, or the diagnostic value was not reported. This limitation results from the lack of standard for reporting omic biomarkers and quality assessment of omic studies Ref. . Future The literature has demonstrated that multi-omic studies can be completed on the same cohort of women. Integration of clinical data with omic biomarkers could lead to predictive models of pregnancy outcome. Our experiences of prospectively recruiting women to a multi-omic study of PTB highlighted the need for a large sample size to retain statistical power at the multi-omic level, whereby samples loss occurred within the individual omic analyses then during multi-omic data integration Refs , 84. StuTo conclude, this review has demonstrated that PTB omic studies have reported biomarkers in concordance with the key risk factor of infection or inflammation, hence suggesting the role of infection or immunological pathway components in initiating early labour. This also highlights the need for multi-omic studies to determine biomarkers and pathways associated with PTB based on interactions between omic layers.


ObjectivesEndoscopic retrograde cholangiopancreatography (ERCP) is frequently used to manage pancreaticobiliary disorders in an inpatient setting. Malnutrition is prevalent among hospitalized patients, and it is generally associated with poor clinical outcomes. However, there is a lack of studies on how malnutrition affects the outcomes of inpatient ERCP. Thus, we investigated the outcomes of inpatient ERCP among patients with malnutrition.MethodsAdult patients who underwent ERCP from the 2014 National Inpatient Sample database were selected to conduct retrospective analysis. Patient demographics and outcomes of ERCP were compared between the groups with and without malnutrition. The outcomes of interest were inpatient mortality, length of stay, total hospital charge, and ERCP complications, including pancreatitis, cholecystitis, cholangitis, sepsis, hemorrhage, and intestinal perforation.ResultsPatients with malnutrition had longer length of stay  and higher total hospital charge . Malnutrition was an independent risk factor for inpatient mortality (adjusted odds ratio (aOR) 2.54, 95% confidence interval (CI): 1.70-3.82, p < 0.05), sepsis , hemorrhage , and intestinal perforation .ConclusionsOur study indicates that patients with malnutrition are more likely to have worse outcomes, such as increased inpatient mortality, sepsis, hemorrhage, and intestinal perforation. Understanding the nutrition status of patients undergoing ERCP can be a useful approach for risk stratification and determining if closer surveillance of the complications is warranted. Endoscopic retrograde cholangiopancreatography (ERCP) is a widely used procedure for the management of pancreaticobiliary disorders such as choledocholithiasis, acute cholangitis, and acute biliary pancreatitis . StudiesAlthough malnutrition may carry different definitions, it can be defined as a state in which inadequate nutrition intake or uptake causes decreased body mass and impaired physical and mental function . MalnutrDue to the high prevalence of malnutrition in hospitalized patients and widespread use of ERCP, patients who undergo ERCP may have malnutrition, which may complicate their hospital courses, given that malnutrition is linked to worse outcomes in general. However, there is a lack of studies that explicitly address how malnutrition affects the inpatient outcomes of ERCP. Thus, this study aims to assess the outcomes of inpatient ERCP among patients with malnutrition.This article was previously presented as a meeting abstract at the American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting in October 2021.This is a retrospective cohort study investigating adult patients (aged 18 and above) who underwent ERCP in an inpatient setting. Data from the National Inpatient Sample (NIS), 2014, Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality, which is known as the largest all-payer inpatient database in the United States, were used . The stuIBM SPSS Statistics for Windows, Version 28.0  was used for all statistical analyses. Chi-squared tests and independent t-tests were performed to compare proportions and means, respectively. Statistical analyses in this study were two-tailed, and a p-value less than 0.05 was considered statistically significant. To determine if malnutrition is an independent predictor of the clinical outcomes adjusting for age, sex, race, and the Charlson Comorbidity Index, multivariate logistic regression analysis was used.Among the 5,664 patients who underwent ERCP, 746 patients had a history of malnutrition. Table Table Odds ratios of clinical outcomes and corresponding p-values after adjusting for age, sex, race, and the Charlson Comorbidity Index are listed in Table This study indicates that malnutrition is associated with higher risks for sepsis, hemorrhage, and intestinal perforation in patients undergoing inpatient ERCP. These worse outcomes can undoubtedly contribute to the higher mortality, length of stay, and total hospital cost, as shown in this study. These results are consistent with previous studies showing the association between malnutrition and increased mortality, length of stay, and hospital charge ,10. HoweAlthough this study shows an overall increased risk of sepsis, the odds ratios of common ERCP-associated infections such as cholangitis and cholecystitis were not statistically different between the groups with and without malnutrition. Cholangitis may develop in the setting of incomplete biliary drainage and stent obstruction or migration, and cholecystitis is thought to be from gallbladder contamination by nonsterile contrast material . The patBleeding related to ERCP is most commonly associated with sphincterotomy and may happen in about 0.3-2.0% of cases . MalnutrPost-ERCP perforation occurs in approximately 0.4% of the cases . MalnutrA retrospective study involving 44 million adult inpatient cases at 460 sites illustrated that oral nutritional supplements reduced length of stay, cost, and readmission risk . HoweverThe data used in this study are obtained from the NIS database, which relies on billing code inputs provided by healthcare providers. Thus, inaccurate billing may result in either a lower or higher number of diagnoses found in the study. In addition, as it only contains inpatient data, delayed outcomes after discharge are not captured. Indication, approach, and the number of attempts of ERCP can alter the outcomes, which also cannot be identified. Nonetheless, the NIS database provides a large sample size to estimate patient characteristics and outcomes at a national level, which is its greatest strength.As malnutrition is common among hospitalized patients, patients who undergo inpatient ERCP may have malnutrition. These patients are at increased risk for worse outcomes, such as increased inpatient mortality, sepsis, hemorrhage, and intestinal perforation. Understanding the potential outcomes of inpatient ERCP in malnourished patients and a thorough evaluation of the patient’s nutritional status to assist with risk stratification for ERCP may ultimately improve outcomes of ERCP in this population.


In recent years, deep learning techniques have excelled in video action recognition. However, currently commonly used video action recognition models minimize the importance of different video frames and spatial regions within some specific frames when performing action recognition, which makes it difficult for the models to adequately extract spatiotemporal features from the video data. In this paper, an action recognition method based on improved residual convolutional neural networks (CNNs) for video frames and spatial attention modules is proposed to address this problem. The network can guide what and where to emphasize or suppress with essentially little computational cost using the video frame attention module and the spatial attention module. It also employs a two-level attention module to emphasize feature information along the temporal and spatial dimensions, respectively, highlighting the more important frames in the overall video sequence and the more important spatial regions in some specific frames. Specifically, we create the video frame and spatial attention map by successively adding the video frame attention module and the spatial attention module to aggregate the spatial and temporal dimensions of the intermediate feature maps of the CNNs to obtain different feature descriptors, thus directing the network to focus more on important video frames and more contributing spatial regions. The experimental results further show that the network performs well on the UCF-101 and HMDB-51 datasets. A great number of videos have been generated as a result of the advancement of multimedia technologies. In recent years, video understanding has emerged as a crucial field of computer vision for better analyzing and understanding video data. Human action recognition is one of the most fundamental tasks in video understanding, which is becoming increasingly popular in surveillance systems , health The original video is cut into different video clips, each with different contributions to action recognition. Some clips have a discriminatory role in the classification, while others may lead to the action classifier being misled. For instance, as shown in Many studies on action recognition concentrate on modeling the temporal and spatial characteristics of the video. The key advantage of convolutional neural networks (CNNs) is their ability to extract spatiotemporal features directly from video frames in an effective manner. Inspired by the successful application of CNNs in image classification  and targWe propose an FSAN model with the ability to model spatiotemporal features of video information. FSAN contains a spurious-3D convolutional network and a two-level attention module that can be easily implemented and embedded into a CNN-based action recognition model with end-to-end training.We design an effective two-level attention module to help exploit information features across channel, time and space dimensions, and a video frame attention module to highlight the more important frames in the entire video sequence to reduce interference due to similarities between heterogeneous action video sequences. The spatial attention module focuses on the more important spatial regions in some given frames.Implementing end-to-end training on two challenging action recognition datasets, UCF101 and HMDB51, FSAN outperforms state-of-the-art video action recognition networks compared to existing methods.In our previous work , as showThe remainder of this paper is organized as follows. In Human action recognition in video has been widely used in areas such as autonomous driving, intelligent security, virtual reality, video parsing, military reconnaissance, sports training aids, etc. It has contributed significantly to the development and progress of many fields, both industrial and military, and has received considerable critical attention. In this section, we present the relevant action recognition models and attention mechanisms respectively.Human action recognition is a hot topic in video understanding. Early work focused on designing a variety of handcrafted features to encode video data ,12,13, pWith the rise of deep learning , the greThe attention mechanism is used by the human visual system to aid with the efficient and effective analysis and interpretation of complicated situations. As a result, researchers have begun to incorporate attention processes into computer vision systems to increase their performance. In recent works, the visual attention mechanism has been widely applied to various CNNs-based models and yielded impressive results in both image ,19,20,21For the field of image recognition, Wang et al.  proposedFor the field of action recognition, by adaptively recalibrating channel feature responses, Chen et al.  proposedIn summary, with deep learning-based video human action recognition, as video data bring temporal information, we need to focus more not only on important features to reduce the interference of information such as noise in the spatial dimension but also on important frames in the temporal dimension. In this section, we make a detailed description of the proposed FSAN. In video action recognition, each video frame contributes differently to the recognition of action categories. Some actions may occur in some concentrated frames, and some actions may occur in some long sustainable sequence of frames. Therefore, not all video frames are relevant to action recognition, and there are some video frames that are less relevant, or even not relevant at all, to the action category. If we feed these interfering frames into the network, this may introduce interference signals such as noise, making the recognition results inaccurate. Conversely, some frames are more relevant to the action category and more attention needs to be paid to these frames. The CNNs for human action recognition are more reliable when it concentrates on shorter but more information-rich sections of the action video rather than all of the video sequence. In order to learn the differentiation function, a frame attention module must be introduced. We compress the channel and spatial dimensions of the input feature map, retaining information in the temporal dimension to extract temporal features, and to obtain temporal descriptors, which are then used to efficiently aggregate frames consisting of information relevant to particular action categories and to generate frame attention scores. As shown in Then, since the bottleneck of our s-resnet has three convolutions, we need to aggregate the feature maps of the three different convolutions, for which we used the function “cat”. Afterwards, we fed the integrated features into a fully connected (FC) layer.Conv1D denotes a one-dimensional convolution, Finally, the output was normalized using the sigmoid function. We can obtain the weights according to the following formula:We may investigate spatial attention at the channel level, which aids in learning discriminative features for action recognition. The individual channels in a convolutional neural network-based model can be considered as spatially appearing representations of specific actions. We created a SAM for learning the relevance score of each channel of a convolutional neural network having a specific action feature, inspired by ECA-Net. The model emphasizes spatial regions with high scores related to particular action categories while suppressing regions with low values that are irrelevant. We feed the output feature map after the FAM module into the SAM module, which is efficiently compressed in both spatial and temporal dimensions to extract channel information and similarly obtain channel descriptors in order to efficiently capture spatial attention maps. Previous techniques have used global averaging pools such as ECA-Net and Se-Net to aggregate geographic information. It is noted in the literature  that usi1 and w2 are trainable parameters, where r is the reduction ratio; Therefore, as shown in All experiments in this paper are based on the Ubuntu 20.04 bionic operating system, with an Intel Xeon E5-2620v4 CPU and a GeForce RTX 2080 Ti GPU. On two benchmark datasets, we conduct extensive experiments in this section. The two benchmark datasets are briefly introduced initially, and then the specifics of the experiments—including data processing, training configuration and inference procedures—are presented. Some ablation studies are followed by several comparison experiments, which are then run and analyzed for our model and the state-of-the-art methods. All experiments were conducted on 4 GeForce RTX 2080 Ti GPUs using PyTorch (3.8).UCF101: The UCF-101 dataset is an action recognition dataset made up of realistic-looking action videos. The dataset, which was compiled from YouTube, consists of 13,320 action video clips from 101 different human action categories. It also includes a range of difficult situations, including dim illumination, crowded backdrops and sharp fluctuations in camera movement. Non-action frames were briefly cut out of the videos. Each video clip is an average of seven seconds long and is broken down into the following five categories: (1) character interaction, (2) body movement, (3) human interaction, (4) playing an instrument and (5) human interaction. Typical action examples in the UCF-101 datasets are shown in HMDB51: The HMDB-51 dataset contains 6766 clips divided into 51 action categories. There are at least 101 clips in each action class, largely from movies but also a few from online video repositories, such as YouTube and Google Video. The dataset faces the difficulty of greater intra-class and lesser inter-class heterogeneity. The average length of the video snippets was 3 s, just like in UCF-101. Similar to UCF-101, the training/test split is used. Actions fall into one of five categories: (1) general facial actions, (2) facial actions involving object manipulation, (3) general body actions, (4) body interactions involving objects and (5) body interactions involving other people. Typical action examples in the HMDB-51 are shown in Using quick video-loading libraries (such as decord and PyAV), we decoded the video more quickly to produce the original frames. Using the decord tool, we extracted the original frames from the movie, sampled them to get 64 consecutive frames and then extracted 8 frames at 8-frame sample intervals. We fed the network clips that are 3 channels by 16 frames by 224 pixels by 224 pixels in size. We employed techniques for data augmentation that are comparable to those in . Random On a four-GPU system, we trained our model 100 epochs. With a momentum of 0.9 and a weight decay of 0.0001, we used stochastic gradient descent (SGD) to train our network model. Our network model was trained from scratch using two datasets. The learning rate was 0.002 at first. We chose dropout with a dropout ratio of 0.5 after the global pooling layer and discovered that activating batch normalization in our application decreases overfitting. In our application, we discovered that turning on batch normalization lessens overfitting. To initialize the weight layers, we employed the technique from .We evaluated the proposed model on two public benchmarks (UCF101 and HMDB51). Then, we extracted 10 clips from the original videos and calculated their action recognition scores in the time domain. The largest classification score indicates the corresponding class label. Finally, we calculated the average of all segment classification scores and recorded it as the result of the test.First, we performed comparative experiments with the baseline without any attention module and with the addition of a frame attention module and a spatial attention module, respectively, with the particular note that the baseline used in the experiments in this paper was s-resnet and the dataset used for the experiments was HMDB-51 (Split1). These two modules are capable of being connected in many ways . In addition, the sequence between the two modules can be swapped at will. Through ablation studies, we have concluded that the optimal architecture of FSAN is that the spatial attention module is followed sequentially by the video frame attention module.The Validation of FAM and SAM. We denote the baseline network as s-resnet50, the network with only the spatial attention module embedded is noted as SAM and, similarly, the network with only the video frame attention module embedded is noted as FAM. We compared the performance of the three in HMDB-51. We investigated three ways of combining models: parallel and fused (F//S), sequential spatial-frame (SF) and sequential frame-spatial (FS).As a result of The Arrangement of FAM and SAM. We investigate three ways of combining models: parallel and fused (F//S), sequential spatial-frame (SF) and sequential frame-spatial (FS). Here, SF means that the spatial attention module precedes the video frame attention module, and conversely, FS means that the video frame attention module precedes the spatial attention module. It can be verified whether assigning spatial weights first is more helpful for action recognition or assigning video frame weights first is more helpful for action recognition.As seen in We compare the performance of our FSAN architecture with other state-of-the-art methods on two action recognition benchmark datasets: UCF-101 and HMDB-51. On the UCF101 and HMDB51 datasets, we fine-tuned the network pre-trained on Kinetics400 or Imagenet. To be fair, we considered an approach with only RGB frames without any additional modalities  as input. The results are shown in As shown in As listed in Our best results outperformed many methods on the HMDB-51 dataset and the UCF-101 dataset, demonstrating the importance of attention mechanisms and the effectiveness of the spatial attention module and frame attention module. In terms of action recognition, our model can distinguish spatiotemporal feature representations, highlight action categories with in-frame and focus on keyframes associated with action categories through space and time. Furthermore, on both datasets, our model also outperforms the latest attention-based approaches such as STA . HoweverIn this paper, a new stacked diverse attention network is proposed. The method uses a 3D CNN to extract basic deep features and then mines discriminative features between actions using the proposed attention model. To better focus on key information and keyframes in the feature graph, a spatial attention module is designed, which is an attention mechanism that gives higher importance scores to spatial regions and video frames that are more relevant to the action category without dimensionality reduction through a local cross-channel interaction strategy. State-of-the-art performance can be achieved in action recognition tasks, and extensive experiments demonstrate the effectiveness of the proposed FSAN. In future research, we would like to investigate how to improve the robustness of the attention mechanism to achieve better performance.


Aims: Workplace stress for support workers in UK hospitals  is poorly understood. This study explores experiences of HCAs working in a National Health Service in-patient dementia unit after 10 years of national financial austerity (2008–2018). Design: Qualitative evaluation. Methods: 15 HCAs (42%) from a specialist dementia care Unit were interviewed. Interviews were guided by UK Health & Safety Executive published dimensions of work stress. Framework analysis was applied to interview transcriptions, corroborated by a follow-up focus group (6 HCAs). Post hoc interviews with 10 nurses were later introduced to obtain a balanced view of teamwork on the Unit. Results: Health care assistants were altruistic regarding demands of dementia care but otherwise negative of most aspects of their work environment. Staff shortages had increased job demands: workload, poor shift rotas, and excessive reliance on inexperienced agency staff. According to HCAs, job resources of the care team were in significant deficit: nurses in charge were perceived as poor team leaders, had poor interpersonal skills, lacked respect for experienced HCAs, and deemed to be frequently absent from the ward so failing to support carers. HCAs’ lack of decision-latitude exacerbated the situation. In contrast, nurses interviewed did not recognise the teamwork issues raised by HCAs, who were considered obstructive, unsupportive, lacked awareness of nurses’ responsibilities, and of insights how understaffing meant excessive administration and time required to support patients’ relatives. Such dissonant inter-group views caused considerable friction and exacerbated the work pressure. Conclusion: Study outcomes spotlighted impacts of socioeconomic issues for HCAs. Staff shortage, exacerbated by financial austerity measures (pre-COVID pandemic), increased job demands for HCAs but their psychosocial job resources were in serious deficit, so putting them at risk of burnout. Inter-group relations are key for a collaborative ethos, and are amenable to interventions. Such difficulties should not be allowed to fester. Around the time of this present study approximately 40% of all staff sickness absence in the UK National Health Service (NHS) was related to work stress . The risIn addition, existing difficulties in recruitment and retention of staff in recent years have led to significant staff shortages that were exacerbated by financial austerity measures introduced in the UK in 2008 . In mentDementia care in the United Kingdom is delivered by a team comprised primarily of unqualified support workers, mainly health care assistants (HCAs), working alongside nurses. Doctors are not regularly based on the wards, only visiting patients for review and/or to admit them. HCAs work directly with patients but rely on the nurse in charge of the team to ensure a fair distribution of work and to provide a strong network of support and risk management. While evaluations have been made of the NHS work environment for qualified staff  the situThe recruitment of care staff to the National Health Service (NHS) had been difficult for many years prior to the time that the study of Schneider et al. 2010) was undertaken . Introdu was undeOne response to the significant shortage of nurses was an increased reliance on support workers, who are less costly to the NHS . Recruitsubmitted for publication) identified just six studies that specifically related to HCAs working in specialist dementia care. Five studies focused on specific issues including emotional labour of care  are advanced in age, they are frail, so you have to put in extra effort and extra care”(HCA 5)“…patients obviously…need our support in nearly everything: toileting, bathing, washing, feeding and a whole lot, and you still must do laundry for them obviously on daily basis. You see, it’s difficult. You can’t compare it with other wards”.(HCA 15)unpredictable moods that could include abuse or sudden aggression. For example, in this study,Patients with advanced dementia also tend to be resistive of day-day care activities complicated further by their “…sometimes, they don’t know you are helping them, and they will start fighting you”(HCA 10)HCAs were mindful of potential risks to themselves:“Sometimes, I’m very concerned because some of the residents or patients have challenging behaviours… when you are going to work and you know you have such huge number of people to deal with and different presentations, yea, you get worried”(HCA 8)Despite the demands and physical risks, the consensus of participants was that such demands and risks were to be expected. HCAs were altruistic about the challenges they faced whilst caring for patients, illustrated by the following comment:“…they’ve lived their lives and at old age they really need to be taken good care of. But I enjoy doing it. Personally, that’s what I like to do”(HCA 3)Rather, the main work-related problems for participants were demands arising from aspects of the work environment. The following comment emphasised the effect this can have:“…the nature of the [work] environment affects how I feel after some shifts; stressed, angry, tired you know.”(HCA 3)Theme 2. Demands of a high workloadmore staff”. Understaffing was suggested to be related to cost-cutting, for exampleHCAs identified high workloads which they attributed to inadequate staffing. HCA4 summed up the problem when asked ‘What would help to make your job, your role even more effective and interesting?’ by simply stating ““…there used to be proper staffing but now maybe they are trying to cut cost. The issue of staffing has not been critically looked at”.(HCA6)Participants emphasised that this led to work intensification, for example,“The demands of the job in a situation… where you are short-staffed then definitely you are going to be stressed where in a situation whereby a workload of 5 people is being done by 3 then definitely you will be stressed”.(HCA 6)The following comment from a very experienced HCA indicated that the dementia Unit was not unusual in this respect:“… the recommendation [in mental health care] is that dementia clients require more staffing support than others. I’m of the opinion that NHS hospitals do not provide that “.(HCA 13)temporary staff. For example,Staff shortage also was perceived as detrimental to allocation of staff to teams on a shift as the shortage meant excessive reliance on “We rely on irregular staff so much…that can be stressful on substantive staff. Not because they are not good at their jobs but because they are not substantive, they don’t know the routines”.(HCA 5)“Sometimes when you see the rota and see people you might be working with… you are so worried about it.(HCA 5)skill mix profile that becomes unbalanced to the effect that HCAs were distracted by having to provide supervision:Relatedly, temporary staff may introduce a “Staff who don’t know the ward, or our patients, are a bit of a pain [problem] really. You’ve got to show them literally everything and that is difficult when you’ve got stuff to do really”.(HCA 14)Supporting inexperienced agency staff also can potentially increase risk of harm to HCAs in the team:“Sometimes you must restrain patients who are aggressive so you might have staff who has not enough training or has not been given an experience? If…. someone just let go, that patient will just hit you ”.(HCA 5)It was suggested that the manager appointing inexperienced agency staff should be more aware of the skill mix consequences:“I think it’s more on the people doing the staff mix. For instance, [the nurse] setting up your ward should know if you are bringing on an agency or someone who is not regular on the ward.”.(HCA 14)That issue extended to perceptions of nurses in charge who also lacked experience:“Lack of experienced staffing is across the board …You can have experienced domestics [HCAs]…that could make all the difference to a team…whereas a charge nurse with maybe no experience….yea, its lack of staffing, lack of experience”.(HCA 4)Theme 3: Demands of poor shift patternstiredness and exhaustion:Staff shortage also had implications for the scheduling of shifts, with a greater application of short shift rotations. Such patterns were a major source of “The shift patterns are horrible. We rarely have enough rest before going back to work. It’s stressful”.(HCA 9)“The shift pattern isn’t healthy at all. It’s physically and mentally draining”.(HCA 8)Unsurprisingly, the scheduling of short shifts had an impact on family life, for example:“…I do not have enough out of work hours after a shift; knowing I’ll be going back to work in few hours and with the same patients and probably staff who are not very helpful, I think we just need more time off the ward for ourselves, families ”.(HCA14)‘Job resources’ should help staff to meet their work responsibilities and stimulate personal and/or professional growth. This study identified deficits that introduced serious challenges for HCAs, particularly with regard to team leadership, in-team relationships and interpersonal factors, so adding to the demands they felt.Theme 4. Team leadershipAs support workers HCAs have little decision-latitude and so look towards nurses to determine the team rota and work allocation for the shift. Good communication therefore was essential in that respect:“The easiest shifts I have are the ones where communication at the beginning of the shift has been clear and concise……[so] you know exactly where you are and what you are doing and who’s doing what”.(HCA 11)poor leadership by nurses was a strong sub-theme for interviewees, as it left them feeling disorganised and confused as to their allocated tasks within the team. Imprecise communication caused a lack of role clarity,, for example:However, “The problem with the stress we face in most areas is when roles are not defined… When roles are not defined, this is when you see people playing around looking for what to do. Some dedicated ones are stressed, and it helps more when people know what to do, when to do it and how to do it”(HCA 11)This participant summarised the situation succinctly,If you have no leadership then, you have no team really…’(HCA 6)lack of autonomy, also identified as an issue by other studies , for example:The effects of poor role clarity were exacerbated by HCAs’ “…if a client is supposed to be on a higher level of observation due to their behaviour, and to keep other clients safe…I can’t put the client on a level of observation, like three to four, without a doctor or other professional group’s input”(HCA 6)Theme 5: Inter-relationships within the teamHCAs were very vocal on issues of team-relations; judging by the number of comments and strength of views regarding this theme possibly was the most significant resource issue for them. Teamwork is reliant upon good team spirit and effective inter-relationships between team members:“Good team spirit helps a shift go well. Even if you are short staffed but the staff on ground are willing to work, it makes it go well”.(HCA 4)group-relations between team members were poor. This could be between HCAs themselves:However, some HCAs identified poor team spirit in the team. Most commented very strongly that “To be honest, some Healthcare Assistants shy away from work. They are lazy and do unimportant stuff, leaving the important ones…Even the nurses themselves don’t like working with them, and this is common among permanent staff”(HCA 13)However, the general opinion of HCAs was that the most significant relationship difficulties were with nurses. One prominent complaint was that nurses were often absent from the ward so unsupportive of HCA colleagues. Time spent in the office means less time on the ward, which some HCAs blamed on authorities who demand a high amount of paperwork from the nurses they work with. For example,“Nurses are under pressure because after shifts some tend to stay and ensure that every paperwork is completed. Apparently, this is pressure coming from top management, CQC [Care Quality Commission] and government”.(HCA 12)avoidance of ward work as it provided a convenient distraction for nurses to minimise their time on the ward. For example:Most interviewees however were sceptical of this explanation and suggested that completing paperwork was an excuse for “Also, there is …this mental disposition by some nurses that they are only there to do medication…after doing medication they…will go and probably sit down and be doing paperwork and they will leave the rest of the work to the support worker”.(HCA 6)One HCA claimed that the diversion of paperwork potentially could have detrimental outcomes, noting quite graphically:”Could you imagine nurses leaving patients in need just to update their paperwork. But this happens all the time. Not nice at all.”.(HCA 2)poor inter-personal skills of some nurses:Further, HCAs also considered that this situation was aggravated by “When you are struggling, you won’t want to ask for assistance because the outcome or the way the person will turn you down will make you feel inferior or incapable, so you won’t want to ask.”.(HCA 6)Theme 6: Lack of Support (Nurses and Managers)demarcation as to their role:Perceptions of poor support permeated HCAs’ views of the work environment, evident in some examples already given above: poor shift work patterns, poor leadership, lack of role clarity. A further strong issue for HCAs was that nurses made a clear “Some…clearly dictate the role ‘I’m a nurse, I’m a nurse’. Even when you are short on the floor, they are not really ready to help and it’s really, really exhausting to see someone not working, not busy but still disturbing you whilst you are carrying out your own responsibility”.(HCA 7)This caused frustration and irritation as it was interpreted as nurses not engaging with personal care for patients:“Sometimes even when HCAs are short staffed… these nurses don’t help.”.(HCA 5)When they are not very busy, what stops them from toileting a patient?(HCA 7)personal well-being was strongly criticised by some. As an example, one HCA was highly critical of a lack of concern or acknowledgement of effects on him following an injury sustained in caring for the patient:Additionally, a perceived poor concern from managers for staff members’ “I had no support, nothing No. I was left literally…seeking support somewhere else from other than my own team”.(HCA 4)This lack of concern was further illustrated by what HCAs considered an abuse of the Bradford ‘Score’, a formula commonly used as a human resource tool to measure the extent of an individual’s absenteeism. Participants perceived a deliberate misinterpretation of the ‘Bradford score’ by managers who they claimed used it as a threat to staff, so causing some to come to work even when they are truly unwell:“I’ve seen people coming to work…that they are unwell, that they shouldn’t have come in, but they are worried about their Bradford Score. It’s like a threat, it’s awful. I can understand why it’s in place and I can understand the reasons behind it, but it’s dealt with very badly”.(HCA 5)Theme 7: Change‘Change’ is a source of stress for employees who are not consulted about impending significant changes to their workplace, and subsequently their roles . Participants appeared reconciled to not being consulted about change in practices that may affect them. One focus group member suggested a feedback forum might be useful“where one can put in your complaint, one can put in your observation… not only a suggestion box… but a functional one”.(FG Participant)However, others were sceptical and noted that even making a complaint or suggestion was unlikely to be taken on board by managers:“If we say something [then] nothing would be done and if you keep on saying, your name would be crossed off if you are bank and not substantive staff. We’ve said things and nothing was done”.(HCA 12)In addition to corroborating individual comments, focus group participants were asked to comment on how they collectively manage their stress in what at times was clearly a tense environment. HCAs appeared reticent to discuss coping strategies suggestive of a lack of availability of anything constructive. Indeed, comments pointed to individuals finding their own way largely through passive approaches. Two themes emerged: Acceptance and Work-home balance.Theme 8: AcceptanceHCAs appeared reconciled to the reality of working on the Unit. The main coping strategy they adopted was a pragmatic acceptance of challenges within a difficult job. The following comment summed up the discussion:“You just get on with it, you got to get on with it. You can’t run away, can you? You don’t have any choice; the work must be done. You just get on with it”.(FG participant)Staff sought frequent, short breaks from the ward as time-out helped them to cope, albeit providing only brief moments of relief. For example,“I take 5-minute breaks at work and that helps. I think more breaks should be encouraged in this job really, it’s so stressful”.(FG participant)Theme 9: Work-home balancecompartmentalise work and home life:Others felt that they were able to “I don’t take it home. It’s not that you don’t care, obviously you have done what you could as soon as I leave I just so yeah someone else is taking them”.(FG participant)anticipate problems and take steps to ensure that unresolved care issues were not left behind after a shift only temporary and they sought a means to help reduce the impact of returning to the workplace:For two group members, though, respite was acknowledged as being “When I leave, I leave and then as soon as I walk through that door, the stress returns. So, if it’s unresolved, then I bring it back to work either by talking it through with colleagues or going to my management team”.(FG participant)Comments from HCAs with regard to team working and inter-staff relations reflected poorly on the nurses in the Unit. Accordingly, this study adopted recommendations ,30 that Nurses were first asked contextual questions in order to identify if their general viewpoints on patient care related to those expressed by HCAs. As with HCAs, the 2009–2018 period also evidenced a decrease in nurses; around the time this study was undertaken there were 35,000–40,000 NHS nurse/midwife vacancies, equivalent to around 11% of posts . Underst“…ehm overall, I think it’s more of nurse staffing on the ward that’s causing a whole lot of problems”(Nurse 4)Nurses also cited patient unpredictability. For example,“The worst part of it is that sometimes, they don’t know you are helping them, and they will start fighting you”.(Nurse 10)Nurses also were asked to comment on the level of stress on a scale of 1–10 and all agreed that they found the workplace stressful. For example,“Yes, it’s stressful. I’ll put between 9 and 10”.(Nurse 7)Whilst many comparisons cannot be made between staff who have different roles and responsibilities, such comments suggest that levels of tension and work pressure had a degree of commonality in these respects.The intention of these interviews was to seek better insights into the team working difficulties identified by HCAs from their perceptions. Nurses at times were complimentary of their HCA colleagues but like many HCAs mostly they were negative as to inter-staff relationships, though their perceptions of the sources of such discord were very different see . It woulThis study evaluated experiences of health care assistants (HCAs) working in an inpatient dementia Unit of a UK National Health Service (NHS) hospital after around 10 years of funding cuts and staff reductions through financial austerity measures in the UK (2008–2019)  and theyDelivering in-patient dementia care is demanding and stressful ,3,17, anIf resources are inadequate then they can themselves become additional demands and hence sources of further stress . In thatOne frustrating factor for HCAs, similarly documented by Schneider et al.  and LloyThe Job Demands-Resources model  suggestsThis study provided a comprehensive evaluation of work environment and stress experiences of HCAs towards the end of national financial austerity measures in the UK (2008–2019). The sample size was modest, though not unusually so for a qualitative study. Additionally, high tensions on the wards may have led some participants to self-select on the basis of negative experiences. This could not be ascertained but the interview sample represented 42% of the estimated number of HCAs either employed substantively or as frequent agency appointments, so likely providing a reasonable profile of the Unit. Further, the follow-up focus group of HCAs incorporated participants who had not been interviewed so giving some confidence in the key themes emerging from the interviews.Health care delivery is sensitive to socio-political issues and to local context  so focusAdditionally, post hoc introduction of interviews with 10 nurses gave added-value as it helped to contextualise team working issues highlighted by HCAs. Though not part of the original design their interviews provided important additional insights into the inter-group relationships between HCAs and nurses.Current findings seem likely to have resonance with other dementia hospitals also seeking to reverse the effects of high staff attrition/inadequate recruitment that has been observed across the NHS in recent years (pre-COVID pandemic). Staffing, team working and leadership are critical to collaboration and quality of care but were deficient and appeared to exacerbate the recognised challenges inherent in delivering dementia care. Review  suggestsStaff shortages are unlikely to be resolved in the near future, especially following impacts of the COVID pandemic. In the interim, interventions could focus on improving psychosocial job resources for HCAs and nurses. A message from this study is that managers should promptly address emerging problems and so defuse subsequent tensions that are counter to the functioning of dementia care teams. Further, consideration ought to be given to the experience of HCAs by engaging them more in planning and delivering their work, and to better support for their personal stress managementCaring for patients with dementia introduces considerable emotional demands for staff but it was the work environment that was more of an issue for Health Care Assistants (HCAs). In this study, work environment demands appeared related to understaffing leading to high workloads, poor shift patterns and skill mix issues caused by excessive reliance on temporary, agency staff, some of whom had not the experience of substantive employees. Deficits in job resources for HCAs were perceived to be poor team leadership, poor inter-group relationships, lack of role clarity, and lack of support especially from nurses in charge of the team. Additionally, HCAs’ status as unqualified support workers was frustrating and, in their view, experienced HCAs could contribute to case discussions as appropriate.According to the Job Demands-Resources model the significant imbalance caused by high job demands and serious deficits in job resources translated into a tense and very challenging workplace that risked stress-related ill-health for HCAs. Taking a dual approach by applying assistive interventions to improve personal resources of health care assistants but at the same time improve their job resources by promoting the psychosocial environment, especially of inter-personal and professional relationships, enhancement of social support and management support, and decision-latitude. These are more immediate, amenable interventions. Present findings from this local application of JD-R theory to an understaffed specialist dementia care unit reinforces such strategy as a useful first step to improving collaboration and team working between health care assistants and nurses.


Alcohol drinking and risk factors for problematic drinking may vary across a lifespan. The objective of this study was to identify risk factors for problematic drinking in men and women in their thirties and forties. Alcohol drinking and potential risk factors for problematic drinking were assessed at ages 30, 34, 42, and 46 in the 1970 British Cohort Study. Multilevel models included 10,079 observations in 3880 men and 9241 observations in 3716 women. In men, formerly smoking, currently smoking, having a degree, having malaise, and having a mother who drank while pregnant were independently associated with increased risk of problematic drinking. In women, formerly smoking, currently smoking, being physically active in one’s leisure time, having a degree, having a managerial or professional occupation, having malaise, and having a mother who drank while pregnant were independently associated with increased risk of problematic drinking. In men and women, cohabiting as a couple was associated with decreased risk of problematic drinking. This study suggests that several risk factors may be associated with problematic drinking in men and women in their thirties and forties. Policy makers should consider the role of modifiable risk factors in the prevention of problematic drinking. Alcohol use and alcohol use disorder are among the leading causes of death and disability worldwide . In EnglThe 1970 British Cohort Study consists of people born in England, Scotland and Wales during a single week in 1970 . The preThe dependent variable was problematic drinking. At ages 30 and 34, the cutting down, being annoyed by criticism, feeling guilty, and eye-openers (CAGE) questionnaire was used to assess problematic drinking . ProblemThe independent variables included six potentially modifiable risk factors for problematic drinking, which were assessed at age 30, age 34, age 42, and age 46: smoking, leisure-time physical activity, highest academic qualification, occupation, cohabiting as a couple, and malaise ,22,23,24melogit command was used to fit multilevel logistic regression models for the binary outcome, problematic drinking. Models were fitted for men and women separately because alcohol drinking trajectories are different in men and women in the United Kingdom [p < 0.001). Problematic drinking, smoking, leisure-time physical activity, highest academic qualification, occupation, cohabiting as a couple, and malaise were time varying variables and all the available data from each wave were used in each model. Mother drinking during pregnancy and father’s occupation were unvarying and the data from the age 10 survey were used in each model. All variables were treated as categorical variables. Few cohort members and few cohort members’ fathers were in unskilled occupations, so the unskilled category and the semi-skilled or skilled category were combined. Multilevel logistic regression models allow for participants to be problematic drinkers at one wave and not another. Nonetheless, we excluded participants with problematic drinking at age 30 in sensitivity analyses because it was thought that they might be more susceptible to problematic drinking at age 34, age 42, or age 46.Repeated measurements of the same individual are highly correlated, so we used the multilevel models that can cope with the problem of correlated observations in longitudinal studies . All ana Kingdom . We usedPotential risk factors were assessed at age 30, age 34, age 42, and age 46. The number of cases of problematic drinking at each age is reported in Potential risk factors were assessed at age 30, age 34, age 42, and age 46. The number of cases of problematic drinking at each age is reported in The objective of the present study was to identify risk factors for problematic drinking in men and women in their thirties and forties. Alcohol drinking and potential risk factors for problematic drinking were assessed during four waves of the 1970 British Cohort Study and sophisticated analyses were used to cope with the problem of correlated observations. In men, formerly smoking, currently smoking, having a degree, having malaise, and having a mother who drank while pregnant were independently associated with increased risk of problematic drinking. In women, formerly smoking, currently smoking, being physically active in one’s leisure time, having a degree, having a managerial or professional occupation, having malaise, and having a mother who drank while pregnant were independently associated with increased risk of problematic drinking. In men and women, cohabiting as a couple was associated with decreased risk of problematic drinking. These findings have important implications for the primary prevention of problematic drinking.Alcohol drinking is only measured at baseline in most prospective cohort studies and it has been suggested that such studies be treated with caution because drinking behavior changes with age . BrittonNicotine activates stress- and reward-related brain regions that may facilitate the transition to compulsive alcohol drinking ; and, smA total of 966,040 adults have been in contact with drug and alcohol treatment services in England since records began in 2005 and by 31 March 2019, 15% were still engaged in treatment, 40% had left and not completed their treatment and not returned, and 45% had completed their treatment and not returned . School-The present study has some limitations. Some variables were self-reported and are subject to biases. Different questionnaires were used to assess problematic drinking in participants’ thirties and forties, which may introduce bias. Primary care data suggest that the 4-item CAGE questionnaire has a sensitivity of 71% and a specificity of 91%, while the 10-item AUDIT questionnaire has a sensitivity of 62% and a specificity of 92% ,37. WhenThis longitudinal study with repeated measurements helps clarify complex associations between potential risk factors and problematic drinking in men and women in their thirties and forties. Formerly smoking, currently smoking, having a degree, having malaise, and having a mother who drank while pregnant may be risk factors for problematic drinking in men. Formerly smoking, currently smoking, being physically active in one’s leisure time, having a degree, having a managerial or professional occupation, having malaise, and having a mother who drank while pregnant may be risk factors in women. Cohabiting may be a negative risk factor for problematic drinking in men and women.