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Acidic pH derived from cancer cells as a double‐edged knife modulates wound healing through DNA repair genes and autophagy


Wound healing is a sequester program that involves diverse cell signalling cascades. Notwithstanding, complete signal transduction pathways underpinning acidic milieu derived from cancer cells is not clear, yet. MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay, fluorescein diacetate/propidium iodide staining, and cell cycle flow cytometry revealed that acidic media decreased cell viability and cell number along with enhanced dead cells and S‐phase arrest in normal fibroblasts. Notably, the trends of intracellular reactive oxygen species production and lactate dehydrogenase release significantly increased with time. It seems the downregulation of Klf4 is in part due to acidosis‐induced DNA damage. It promoted cells towards S‐phase arrest and diminished cell proliferation. Klf4 downregulation had a direct correlation with the P53 level while acidic microenvironment promotes cells towards cell death mechanisms including apoptosis and autophagy. Noteworthily, the unchanged levels of Rb and Mlh1 indicated in those genes had no dominant role in the repairing of DNA damage in fibroblasts treated with the acidic microenvironment. Therefore, cells owing to not entering to mitosis and accumulation of DNA damage were undergone cell death to preserve cell homeostasis. Since acidic media decreased the level of tumour suppressor and DNA repair genes and altered the normal survival pathways in fibroblasts, caution should be exercised to not lead to cancer rather than wound healing.

Pressure ulcer Cat. II‐IV incidence on the CuroCell S.A.M. PRO powered reactive air support surface in a high‐risk population: A multicentre cohort study in 12 Belgian nursing homes


The primary objective was to study pressure ulcer (PU) category II‐IV (including suspected deep tissue injury and unstageable PUs) cumulative incidence and PU incidence density, in a 30day observation period, associated with the use of the CuroCell S.A.M. PRO powered reactive air support surface in nursing home residents at risk for PU development. Secondary objectives were to study (a) PU category I cumulative incidence and PU incidence density and (b) user (caregivers and residents) experiences and perceptions of comfort associated with the use of the support surface under study. A multicentre cohort study was set up in 37 care units of 12 Belgian nursing homes. The sample consisted of 191 residents at risk of PU development (Braden score ≤ 17). The cumulative PU incidence was 4.7% (n = 9). The PU incidence density was 1.7/1000 observation days (9 PU/5370 days). The experience and perceptions of comfort analysis revealed that the CuroCell S.A.M. PRO powered reactive air support surface was comfortable for daily use. The mode of action and the quietness of the pump function had a positive impact on sleep quality. Patient comfort and sleep quality are essential criteria in the selection of a support surface.

Translation, cross‐cultural adaptation and validation of the “Cardiff wound impact schedule,” a wound‐specific quality of life instrument, to the native Spanish of Mexican patients

International Wound Journal Translation, cross‐cultural adaptation and validation of the “Cardiff wound impact schedule,” a wound‐specific quality of life instrument, to the native Spanish of Mexican patients


The aim of this study was to translate into Mexican Spanish, cross‐culturally adapt and validate the wound‐specific quality of life (QoL) instrument Cardiff wound impact schedule (CWIS) for Mexican patients. This instrument went through the full linguistic translation process based on the guidelines of Beaton et al (Beaton DE, Bombardier C, Guillemin F, Ferraz MB, Guidelines for the process of cross‐cultural adaptation of self‐report measures, Spine Phila Pa, 1976, 2000, 318‐391). We included a total of 500 patients with chronic leg ulcers. The expert committee evaluated the Face validity and they agreed unanimously that the instrument was adequate to assess the QoL of these patients, covering all relevant areas presented by them. The content validity index obtained was of 0.95. The construct validity demonstrated moderately significant correlations between related sub‐scales of CWIS and SF‐36 (P = .010 to P < .001). The instrument was able to discriminate between healed and unhealed ulcers. The instrument obtained an overall Cronbach's alpha of .952, corresponding to an excellent internal consistency (.903‐.771 alpha range for domains). The CWIS can be appropriately used to assess the health‐related QoL of Mexican patients with chronic leg ulcers.

The effectiveness of pressure ulcer prevention programme: A comparative study


Hospital‐acquired pressure ulcers (HAPUs) affect patients during hospitalisation, putting patients at risk for further complications. HAPU is one of the hospital quality indicators that require quality initiatives or programmes to minimise its occurrence and consequences. The aim of this study was to assess the effectiveness of a developed quality improvement programme in preventing HAPUs. This is a retrospective comparative study, which tracked the outcomes of pressure ulcer prevention programme (PUPP) for 5 years from 2014 to 2018. Data from 50 441 patients were collected from different units in a tertiary hospital in the eastern region of Saudi Arabia. The programme focused on building a wound care team; providing education to hospital staff, patients, and their families; and continuous data monitoring, in addition to follow‐up visits after discharge. Implementation of the programme was successful showing a statistically significant reduction of HAPUs from 0.20% in 2014 to 0.06% in 2018 (P value <.001). The PUPP was effective in reducing the percentage of pressure ulcer cases. The programme can be extended and implemented in other hospitals.

Predictive model to identify the risk of losing protective sensibility of the foot in patients with diabetes mellitus


Diabetic neuropathy is defined as the presence of symptoms and signs of peripheral nerve dysfunction in diabetics. The aim of this study is to develop a predictive logistic model to identify the risk of losing protective sensitivity in the foot. This descriptive cross‐sectional study included 111 patients diagnosed with diabetes mellitus. Participants completed a questionnaire designed to evaluate neuropathic symptoms, and multivariate analysis was subsequently performed to identify an optimal predictive model. The explanatory capacity was evaluated by calculating the R 2 coefficient of Nagelkerke. Predictive capacity was evaluated by calculating sensitivity, specificity, and estimation of the area under the receiver operational curve. Protective sensitivity loss was detected in 19.1% of participants. Variables associated by multivariate analysis were: educational level (OR: 31.4, 95% CI: 2.5‐383.3, P = .007) and two items from the questionnaire: one related to bleeding and wet socks (OR: 28.3, 95% CI: 3.7‐215.9, P = .001) and the other related to electrical sensations (OR: 52.9, 95% CI: 4.3‐643.9, P = .002), which were both statistically significant. The predictive model included the variables of age, sex, duration of diabetes, and educational level, and it had a sensitivity of 81.3% and a specificity of 95.5%. This model has a high predictive capacity to identify patients at risk of developing sensory neuropathy.

Rapid detection of biofilm by wound blotting following sharp debridement of chronic pressure ulcers predicts wound healing: A preliminary study


For optimal wound bed preparation, wound debridement is essential to eliminate bacterial biofilms. However, it is challenging for clinicians to determine whether the biofilm is completely removed. A newly developed biofilm detection method based on wound blotting technology may be useful. Thus, we aimed to investigate the effect of biofilm elimination on wound area decrease in pressure ulcers, as confirmed using the wound blotting method. In this retrospective observational study, we enrolled patients with pressure ulcers who underwent sharp debridement with pre‐ and post‐debridement wound blotting. Biofilm was detected on the nitrocellulose membrane using ruthenium red or alcian blue staining. Patients were included if the test was positive for biofilm before wound debridement. Percent decrease in wound area after 1 week was calculated as an outcome measure. We classified the wounds into a biofilm‐eliminated group and a biofilm‐remaining group based on the post‐debridement wound blotting result. Sixteen wound blotting samples from nine pressure ulcers were collected. The percent decrease in wound area was significantly higher in the biofilm‐eliminated group (median: 14.4%, interquartile range: 4.6%‐20.1%) than in the biofilm‐remaining group (median: −14.5%, interquartile range: −25.3%‐9.6%; P = .040). The presence of remaining biofilms was an independent predictor for reduced percent decrease in wound area (coefficient = −22.84, P = .040). Biofilm‐based wound care guided by wound blotting is a promising measure to help clinicians eliminate bacterial bioburden more effectively for wound area reduction.

Factors influencing the local cure rate of hidradenitis suppurativa following wide local excision


Wide local excision is the gold standard and only potential curative therapy for recalcitrant hidradenitis suppurativa. However, high recurrence rates persist even post‐surgery with little known on the influencing factors for remission. We evaluated the effect of patient, disease, and operative factors on local cure rate of moderate to severe hidradenitis following wide local excision. We performed a retrospective chart review for all patients who had undergone surgical excision of hidradenitis at a university hospital from 2012 to 2018. We identified 79 patients with a total of 220 operative sites. The majority were obese (mean body mass index [BMI] 32.5), female (71%), African‐American (84%), and had a mean age of 31 years. A quarter of operative sites experienced a recurrence (n = 56). Patients who achieved remission had a significantly lower number of affected regions than those who experienced a recurrence (2.3 vs 3.6, P = .0023). Additionally, recurrence rate differed significantly between body locations (P = .0440). Smoking, BMI, Hurley grade, closure method, and excision size did not influence local cure rate. Surgical excision remains a worthy management option for hidradenitis patients with three quarters achieving remission after a single operation. Number of affected regions and location of hidradenitis may play a factor in recurrence.

Use of maggot debridement therapy in hospitalised patients in Germany


Exact data regarding the clinical role of maggot debridement therapy (MDT) for wound care in a specific country are not available. Thus, we analysed the use of MDT in hospitalised patients in Germany. Detailed lists of all hospitalised cases treated with MDT in Germany for the years 2011 to 2016 were provided by the Federal Statistical Office as well as the lists of the 15 most frequent principal and additional diagnoses, respectively, and the 10 most frequent procedures documented with MDT in 2016. Within the 6‐year time period of the study, the number of cases treated with MDT increased by 11% from 4513 in 2011 to 5.017 in 2016. Lower leg and foot were the most frequent anatomic sides of treatment counting up to 83.9% of all cases. In addition, MDT procedures for temporary soft tissue coverage including negative pressure wound therapy were often performed: for treatment of large areas in 36.7% and small areas in 6.2%. 41.3% of all cases treated with MDT had infection with Escherichia coli and 35.9% of all cases with Bacillus fragilis. Our analysis shows a limited use of MDT with a small increase only in the last 6 years in German hospitals. MDT is predominately used to treat foot or leg ulcers.

Peripheral arterial disease screening and diagnostic practice: A scoping review


Early reliable, valid screening, diagnosis, and treatment improve peripheral arterial disease outcomes, yet screening and diagnostic practices vary across settings and specialties. A scoping literature review described reliability and validity of peripheral ischaemia diagnosis or screening tools. Clinical studies in the PUBMED database January 1, 1970, to August 13, 2018, were reviewed summarising ranges of reliability and validity of peripheral ischaemia diagnostic and screening tools for patients with non‐neuropathic lower leg ischaemia. Peripheral ischaemia screening and diagnostic practices varied in parameters measured such as timing, frequency, setting, ordering clinicians, degree of invasiveness, costs, definitions, and cut‐off points informing clinical and referral decisions. Traditional ankle/brachial systolic blood pressure index <0.9 was a reliable, valid lower leg ischaemia screening test to trigger specialist referral for detailed diagnosis. For patients with advanced peripheral ischaemia or calcified arteries, toe‐brachial index, claudication, or invasive angiographic imaging techniques that can have complications were reliable, valid screening, and diagnostic tools to inform management decisions. Ankle/brachial index testing is sufficiently reliable and valid for use during routine examinations to improve timing and consistency of peripheral ischaemia screening, triggering prompt specialist referral for more reliable, accurate Doppler, or other diagnosis to inform treatment decisions.

Sociodemographic and culture results of paediatric burns


Paediatric burn wounds are challenging conditions to manage for both the doctors and patients and can cause several complications entailing a complicated treatment and recovery process. This study aims to evaluate sociodemographic conditions and antibiogram culture results of paediatric burn wounds. Our study retrospectively evaluated 419 paediatric patients with burns regarding age, gender, burn area and degree, total days spent in hospital, surgical history, final condition, additional disease history, previous attempts, and culture results with their antibiotic resistances, haemogram results, C‐reactive protein results, sociocultural conditions, burned region of the body, and structure of the burn. The prominent observations were an increased rate of incidence in male patients and patients with low socioeconomic conditions, the highest incidence of burns from scalding and domestic accidents, and the highest incidence of third‐degree burns. Furthermore, even though the most encountered burn types were extremity burns, the burn types with the highest culture growth ratio were the perineum burns. The dominant culture growth bacterial group was coagulase‐negative staphylococcus, and the ratio of medication resistance was 67.8%. It is imperative to raise awareness regarding domestic accidents to prevent paediatric burn wounds. The mortality risk can be reduced by carefully monitoring multiple organ involvement and providing timely treatment. Moreover, appropriate wound care is warranted to avoid infection from skin flora.

Retinoic acid-stimulated ERK1/2 pathway regulates meiotic initiation in cultured fetal germ cells

by Sung-Min Kim, Toshifumi Yokoyama, Dylan Ng, Ferhat Ulu, Yukiko Yamazaki

In murine fetal germ cells, retinoic acid (RA) is an extrinsic cue for meiotic initiation that stimulates transcriptional activation of the Stimulated by retinoic acid gene 8 (Stra8), which is required for entry of germ cells into meiotic prophase I. Canonically, the biological activities of RA are mediated by nuclear RA receptors. Recent studies in somatic cells found that RA noncanonically stimulates intracellular signal transduction pathways to regulate multiple cellular processes. In this study, using a germ cell culture system, we investigated (1) whether RA treatment activates any mitogen-activated protein kinase (MAPK) pathways in fetal germ cells at the time of sex differentiation, and (2) if this is the case, whether the corresponding RA-stimulated signaling pathway regulates Stra8 expression in fetal germ cells and their entry into meiosis. When XX germ cells at embryonic day (E) 12.5 were cultured with RA, the extracellular-signal-regulated kinase (ERK) 1/2 pathway was predominantly activated. MEK1/2 inhibitor (U0126) treatment suppressed the mRNA expressions of RA-induced Stra8 and meiotic marker genes (Rec8, Spo11, Dmc1, and Sycp3) in both XX and XY fetal germ cells. Furthermore, U0126 treatment dramatically reduced STRA8 protein levels and numbers of meiotic cells among cultured XX and XY fetal germ cells even in the presence of RA. Taken together, our results suggest the novel concept that the RA functions by stimulating the ERK1/2 pathway and that this activity is critical for Stra8 expression and meiotic progression in fetal germ cells.

Cerebellum-mediated trainability of eye and head movements for dynamic gazing

by Akiyoshi Matsugi, Naoki Yoshida, Satoru Nishishita, Yohei Okada, Nobuhiko Mori, Kosuke Oku, Shinya Douchi, Koichi Hosomi, Youichi Saitoh


To investigate whether gaze stabilization exercises (GSEs) improve eye and head movements and whether low-frequency cerebellar repetitive transcranial magnetic stimulation (rTMS) inhibits GSE trainability.


25 healthy adults (real rTMS, n = 12; sham rTMS, n = 13) were recruited. Real or sham rTMS was performed for 15 min (1 Hz, 900 stimulations). The center of the butterfly coil was set 1 cm below the inion in the real rTMS. Following stimulation, 10 trials of 1 min of a GSE were conducted at 1 min intervals. In the GSE, the subjects were instructed to stand upright and horizontally rotate their heads according to a beeping sound corresponding to 2 Hz and with a gaze point ahead of them. Electrooculograms were used to estimate the horizontal gaze direction of the right eye, and gyroscopic measurements were performed to estimate the horizontal head angular velocity during the GSE trials. The percentage change from the first trial of motion range of the eye and head was calculated for each measurement. The percent change of the eye/head range ratio was calculated to assess the synchronous changes of the eye and head movements as the exercise increased.


Bayesian two-way analysis of variance showed that cerebellar rTMS affected the eye motion range and eye/head range ratio. A post hoc comparison (Bayesian t-test) showed evidence that the eye motion range and eye/head range ratio were reduced in the fifth, sixth, and seventh trials compared with the first trial sham stimulation condition.


GSEs can modulate eye movements with respect to head movements, and the cerebellum may be associated with eye–head coordination trainability for dynamic gazing during head movements.

Carvedilol improves glucose tolerance and insulin sensitivity in treatment of adrenergic overdrive in high fat diet-induced obesity in mice

by Linh V. Nguyen, Quang V. Ta, Thao B. Dang, Phu H. Nguyen, Thach Nguyen, Thi Van Huyen Pham, Trang HT. Nguyen, Stephen Baker, Trung Le Tran, Dong Joo Yang, Ki Woo Kim, Khanh V. Doan

Catecholamine excess reflecting an adrenergic overdrive of the sympathetic nervous system (SNS) has been proposed to link to hyperleptinemia in obesity and may contribute to the development of metabolic disorders. However, relationship between the catecholamine level and plasma leptin in obesity has not yet been investigated. Moreover, whether pharmacological blockade of the adrenergic overdrive in obesity by the third-generation beta-blocker agents such as carvedilol could help to prevent metabolic disorders is controversial and remains to be determined. Using the high fat diet (HFD)-induced obese mouse model, we found that basal plasma norepinephrine, the principal catecholamine as an index of SNS activity, was persistently elevated and highly correlated with plasma leptin concentration during obesity development. Targeting the adrenergic overdrive from this chronic norepinephrine excess in HFD-induced obesity with carvedilol, a third-generation beta-blocker with vasodilating action, blunted the HFD-induced hepatic glucose over-production by suppressing the induction of gluconeogenic enzymes, and enhanced the muscular insulin signaling pathway. Furthermore, carvedilol treatment in HFD-induced obese mice decreased the enlargement of white adipose tissue and improved the glucose tolerance and insulin sensitivity without affecting body weight and blood glucose levels. Our results suggested that catecholamine excess in obesity might directly link to the hyperleptinemic condition and the therapeutic targeting of chronic adrenergic overdrive in obesity with carvedilol might be helpful to attenuate obesity-related metabolic disorders.

Incidence patterns of orofacial clefts in purebred dogs

by Nicholas Roman, Patrick C. Carney, Nadine Fiani, Santiago Peralta

Cleft lip (CL), cleft palate (CP) and cleft lip and palate (CLP) are the most common types of orofacial clefts in dogs. Orofacial clefts in dogs are clinically relevant because of the associated morbidity and high newborn mortality rate and are of interest as comparative models of disease. However, the incidence of CL, CP and CLP has not been investigated in purebred dogs, and the financial impact on breeders is unknown. The aims of this study were to document the incidence patterns of CL, CP and CLP in different breeds of dogs, determine whether defect phenotype is associated with skull type, genetic cluster and geographic location, and estimate the financial impact in breeding programs in the United States by means of an anonymous online survey. A total of 228 orofacial clefts were reported among 7,429 puppies whelped in the 12 preceding months. Breeds in the mastiff/terrier genetic cluster and brachycephalic breeds were predisposed to orofacial clefts. Certain breeds in the ancient genetic cluster were at increased odds of orofacial clefts. Male purebred dogs were at increased odds of CPs. Results confirm that brachycephalic breeds are overrepresented among cases of orofacial clefts. Furthermore, geographic region appeared to be a relevant risk factor and orofacial clefts represented a considerable financial loss to breeders. Improved understanding of the epidemiology of orofacial clefts (frequency, causes, predictors and risk factors) may help in identifying ways to minimize their occurrence. Information gained may potentially help veterinarians and researchers to diagnose, treat and prevent orofacial clefts.

Voluntary medical male circumcision for HIV prevention among adolescents in Kenya: Unintended consequences of pursuing service-delivery targets

by Adam Gilbertson, Barrack Ongili, Frederick S. Odongo, Denise D. Hallfors, Stuart Rennie, Daniel Kwaro, Winnie K. Luseno


Voluntary medical male circumcision (VMMC) provides significant reductions in the risk of female-to-male HIV transmission. Since 2007, VMMC has been a key component of the United States President’s Emergency Plan for AIDS Relief’s (PEPFAR) strategy to mitigate the HIV epidemic in countries with high HIV prevalence and low circumcision rates. To ensure intended effects, PEPFAR sets ambitious annual circumcision targets and provides funding to implementation partners to deliver local VMMC services. In Kenya to date, 1.9 million males have been circumcised; in 2017, 60% of circumcisions were among 10-14-year-olds. We conducted a qualitative field study to learn more about VMMC program implementation in Kenya.

Methods and results

The study setting was a region in Kenya with high HIV prevalence and low male circumcision rates. From March 2017 through April 2018, we carried out in-depth interviews with 29 VMMC stakeholders, including “mobilizers”, HIV counselors, clinical providers, schoolteachers, and policy professionals. Additionally, we undertook observation sessions at 14 VMMC clinics while services were provided and observed mobilization activities at 13 community venues including, two schools, four public marketplaces, two fishing villages, and five inland villages. Analysis of interview transcripts and observation field notes revealed multiple unintended consequences linked to the pursuit of targets. Ebbs and flows in the availability of school-age youths together with the drive to meet targets may result in increased burdens on clinics, long waits for care, potentially misleading mobilization practices, and deviations from the standard of care.


Our findings indicate shortcomings in the quality of procedures in VMMC programs in a low-resource setting, and more importantly, that the pursuit of ambitious public health targets may lead to compromised service delivery and protocol adherence. There is a need to develop improved or alternative systems to balance the goal of increasing service uptake with the responsible conduct of VMMC.

One simple claudication question as first step in Peripheral Arterial Disease (PAD) screening: A meta-analysis of the association with reduced Ankle Brachial Index (ABI) in 27,945 subjects

by Arne Georg Kieback, Christine Espinola-Klein, Claudia Lamina, Susanne Moebus, Daniel Tiller, Roberto Lorbeer, Andreas Schulz, Christa Meisinger, Daniel Medenwald, Raimund Erbel, Alexander Kluttig, Philipp S. Wild, Florian Kronenberg, Knut Kröger, Till Ittermann, Marcus Dörr

Purpose and methods

A meta-analysis using data from seven German population-based cohorts was performed by the German Epidemiological consortium of Peripheral Arterial Disease (GEPArD) to investigate whether one question about claudication is more efficient for PAD screening than established questionnaires. Claudication was defined on the basis of the answer to one question asking for pain in the leg during normal walking. This simple question was compared with established questionnaires, including the Edinburgh questionnaire. The associations of claudication with continuous ABI values and decreased ABI were analyzed by linear and logistic regression analysis, respectively. The results of the studies were pooled in a random effect meta-analysis, which included data from 27,945 individuals (14,052 women, age range 20–84 years).


Meta-analysis revealed a significant negative association between claudication and ABI, which was stronger in men (β = -0.07; 95%CI -0.10, -0.04) than in women (β = -0.02; 95%CI -0.02, -0.01). Likewise, the presence of claudication symptoms was related to an increased odds of a decreased ABI in both men (Odds ratio = 5.40; 95%CI 4.20, 6.96) and women (Odds ratio = 1.99; 95%CI 1.58, 2.51).


Asking only one question about claudication was able to identify many individuals with a high likelihood of a reduced ABI with markedly higher sensitivity and only slightly reduced specificity compared to more complex questionnaires. At least in men, this question should be established as first screening step.

Psychological and physiological effects of applying self-control to the mobile phone

by David M. Markowitz, Jeffrey T. Hancock, Jeremy N. Bailenson, Byron Reeves

This preregistered study examined the psychological and physiological consequences of exercising self-control with the mobile phone. A total of 125 participants were randomly assigned to sit in an unadorned room for six minutes and either (a) use their mobile phone, (b) sit alone with no phone, or (c) sit with their device but resist using it. Consistent with prior work, participants self-reported more concentration difficulty and more mind wandering with no device present compared to using the phone. Resisting the phone led to greater perceived concentration abilities than sitting without the device (not having external stimulation). Failing to replicate prior work, however, participants without external stimulation did not rate the experience as less enjoyable or more boring than having something to do. We also observed that skin conductance data were consistent across conditions for the first three-minutes of the experiment, after which participants who resisted the phone were less aroused than those who were without the phone. We discuss how the findings contribute to our understanding of exercising self-control with mobile media and how psychological consequences, such as increased mind wandering and focusing challenges, relate to periods of idleness or free thinking.