Bifunctional degraders of cyclin dependent kinase 9 (CDK9): Probing the relationship between linker length, properties, and selective protein degradation.

Cyclin-dependent kinase 9 (CDK9) is a promising therapeutic target in multiple cancer types, including acute myeloid leukemia (AML). Protein degraders, also known as proteolysis targeting chimeras (PROTACs), have emerged as tools for the selective degradation of cancer targets, including CDK9, complementing the activity of traditional small-molecule inhibitors. These compounds typically incorporate previously reported inhibitors and a known E3 ligase ligand to induce ubiquitination and subsequent degradation of the target protein. Although many protein degraders have been reported in the literature, the properties of the linker necessary for efficient degradation still require special attention. In this study, a series of protein degraders was developed, employing the clinically tested CDK inhibitor AT7519. The purpose of this study was to examine the effect that linker composition, specifically chain length, would have on potency. In addition to establishing a baseline of activity for various linker compositions, two distinct homologous series, a fully alkyl series and an amide-containing series, were prepared, demonstrating the dependence of degrader potency in these series on linker length and the correlation with predicted physicochemical properties.

Descripción de los pacientes atendidos en la Escuela de Prevención de Fracturas y Caídas en el contexto de una Fracture Liaison Service. FLS Anoia / Description of the patients attended at the Fracture and Falls Prevention School in the context of a Fracture Liaison Service. FLS Anoia

Objetivo: El objetivo de este estudio es presentar la actuación, tratamiento y resultados funcionales obtenidos en una Unidad de Prevención de Fracturas y Caídas.Material y métodos: Estudio prospectivo descriptivo de pacientes, con fractura osteoporótica previa, atendidos entre el 25 de abril de 2016 y el 20 de noviembre de 2017.Resultados: Se han analizado 43 pacientes con edad media 80,2 años (DS±5,19), mujeres 81,40% (n=35). Número de fracturas 61, 28% de cadera (n=17), 25% vertebrales (n=15) y 21% distales de radio (n=13). Al alta mejoran todas las escalas de valoración utilizadas, destacando los resultados del SPPB (39,80%), TUG (30,66%) y Tinetti (21,60%).Conclusiones: El paciente atendido corresponde a mujer de 80,2 años, con fractura de cadera, Tinetti 22:09, Daniels en Extremidades de 3,95, 4:05, 3,81, 3,91, SPPB de 6,63, TUG de 17,81 y FIM de 87,19 puntos.Se objetiva mejora en la puntuación de todas las escalas valoradas. (AU)

A prospective study on the effect of coronal tooth structure loss on the 4-year clinical survival of root canal retreated teeth and retrospective validation of the Dental Practicality Index.

AIM: First, to examine the impact of the residual volume of coronal tooth structure in posterior teeth measured with an intra-oral scanner on the 4-year clinical survival of root canal retreated teeth. Secondly, to assess retrospectively the effectiveness of the Dental Practicality Index (DPI) in predicting the survival of root canal retreated teeth. METHODOLOGY: A total of 156 posterior root canal treated teeth (140 patients) had baseline periapical radiographs (PA) and cone-beam computed tomography (CBCT) scans taken prior to root canal retreatment. These teeth were followed up with a clinical examination at 1, 2, 3 and 4 years (T12, T24, T36 and T48) with periapical radiographs and CBCT images taken at T12, and PA taken at T24, T36 and T48 where appropriate. Root canal retreated teeth were dichotomized into 'survived' versus 'extracted'. Fisher's exact test was used to determine the association between the volume of remaining coronal tooth structure and the 4-year tooth survival. The Dental Practicality Index for each tooth was established using the preoperative clinical and radiographical data. Fisher's exact test was used to establish a relationship between categorical variables, the total score of DPI vs tooth outcome. RESULTS: The percentage of extractions associated with teeth with <29.5% remaining coronal tooth structure was 3 times higher (12.5%) compared to that of teeth with a residual tooth structure > 29.5% (3.5%), but with no significant difference (P = 0.073). There was a significant correlation between the outcome of root canal retreatments at 1 year, assessed by both PA and CBCT, and the 4-year survival (Fisher's exact test, P = 0.007 and P = 0.001, respectively). Teeth with DPI scores ≥ 6 were more likely to be extracted than teeth with DPI score < 6 (18.8% vs. 3.9%) (Fisher's exact test, P = 0.045). CONCLUSION: Teeth with <30% of remaining tooth structure were associated with a survival rate above 80% and teeth with more than 30% of residual tooth structure survived in more than 94% of the cases. The radiographic outcome of root canal treatment can also help to predict tooth survival with teeth having an unfavourable outcome at 1 year more likely to be extracted within 4 years of completion of treatment. The DPI score can potentially be used to identify teeth with failed root canal treatment, which are likely to be extracted following retreatment and cuspal coverage.

The role of architectural design for rheumatic patients' wellbeing: the point of view of Environmental Psychology.

Rheumatic diseases (RD) are among the most frequent disorders in the population and the major causes of chronic pain and disability. The resulting consequences are catastrophic, leading to a significant socio-economic burden, which includes significant reductions in quality of life (QoL) and limitations in regular work and daily activities of patients. In spite of this, rheumatic diseases are often misunderstood or diagnosed late, probably due to their characteristics of silent diseases, sometimes unrecognizable to unaffected or unskilled people. Actually, it is surprising that, despite their consequences on QoL and on individual impact, rheumatic diseases are underestimated by the public opinion, which is probably more attracted by other major diseases causing death. This silent perception can even be seen in some among the most recent psycho-social approaches to population needs in the fields of Health Psychology and Environmental Psychology. The latter, also known as Architectural Psychology, is a branch of Psychology that analyses the effects of the built environment on humans, including those affected by diseases. Paradoxically, in many cases, some components of the environments created to protect individuals and/or the population may represent barriers and subsequently causes of disability and suffering in patients with rheumatic diseases. In order to increase awareness about this particular aspect of social life, HEMOVE Onlus, a non-profit association, has promoted the creation of a multidisciplinary Task Group, which included mainly rheumatologists, psychologists and architects, with the aim of applying also for the benefit of rheumatic patients the most modern technical skills available in the context of Environmental Psychology, including in particular design and information technology.

Strategies to improve survival outcomes of out-of-hospital cardiac arrest (OHCA) given a fixed budget: A simulation study.

BACKGROUND: Our study aimed to identify a strategy that maximizes survival upon hospital discharge or 30-days post out-of-hospital cardiac arrest (OHCA) in Singapore for fixed investments of S$1, S$5, or S$10 million. Four strategies were compared: (1) no additional investment; (2) reducing response time via leasing of more ambulances; (3) increasing number of people trained in cardiopulmonary resuscitation (CPR); and (4) automated external defibrillators (AED). METHODS: We estimated the effect of ambulance response time, bystander CPR and AED on survival based on Singapore's 2010-2015 OHCA registry data. We simulated the changes in ambulance response times and likelihood of (1) CPR and (2) AED usage as a function of their increased availability, which was then combined with the effect of each factor to determine the increase in survival for each strategy. RESULTS: Survival given no additional investment was 4.03% (95% CI: 3.96%, 4.10%). The investments in ambulances, CPR training and AEDs for a given budget of S$1M changed survival to 4.03% (95% CI: 3.96%, 4.10%), 4.04% (95% CI: 3.98%, 4.11%), and 4.44% (95% CI: 4.35%, 4.54%), respectively. This generated 0, 2 and 102 additional life years saved respectively. Given a budget of S$5M or S$10M, 509 or 886 additional life years could be saved, by investing in an additional 10,000 or 20,000 AEDs respectively. The strategies reached a saturation effect whereby improvement in survival was marginal when the budget was increased to ≥S$5M for investment in ambulances and CPR training. CONCLUSIONS: Investing in AEDs had the most gain in survival.

Prevalence of low back pain and its effect on health-related quality of life in 409 scholar adolescents from the Veneto region.

Low back pain (LBP) is a common condition with profound effects on well-being. We aimed to define the prevalence and the characteristics of LBP and to investigate its impact on the quality of life (QoL) of 409 students (265 females and 144 males), all high-school adolescents from the Veneto region. LBP was measured with a structured, self-report questionnaire, while the SF-36 questionnaire was used to measure physical and mental QoL. 253 students (61.3%) reported one or more episodes of LBP, with female predominance. Adolescents with LBP treated with drugs and rehabilitation cares have significantly poor belief in pain resolution (p=0.005), but more belief in a prevention program (p=0.006) than the others. After adjustment for sex, a significant association between the SF-36 dimension of vitality and the presence of LBP in males was observed. All SF-36 domains except mental health were significantly higher in females with LBP. Our study confirmed that LBP is frequent in Italian scholar adolescents and has an impact on QoL. Strategies for reducing the effects of LBP on QoL should be an important purpose for clinicians and health policy makers.

The orthodontic-oral surgery interface. Part two: diagnosis and management of anomalies in eruption and transpositions.

The orthodontic-oral surgery interface is important for the multidisciplinary management of patients presenting with complex dental anomalies. This article provides an overview of anomalies of eruption and transpositions, their diagnosis, aetiology, presenting features and the different management options. It also highlights the role of the general dental practitioner (GDP) in identifying such anomalies and the importance of timely referral to specialist care.

Risk estimation of second primary cancers after breast radiotherapy.

AIMS: There is evidence towards the induction of second primary cancers (SPCs) after breast radiotherapy (RT). Organs, such as the lungs and the esophagus, have been identified as common sites for SPC formation. As a result, the current study investigated the risk of secondary carcinogenesis associated with particular RT techniques for breast cancer; including whole breast, segmented breast, partial breast and mammosite brachytherapy. METHODS: In this study, seven breast cancer patients had all major organs contoured on their planning computed tomography (CT) images. Whole breast, segmented breast, accelerated partial breast irradiation (APBI) and mammosite boost treatment plans were generated for each patient using Pinnacle3 treatment planning system. Differential dose-volume histograms were generated for a number of critical structures: bladder, brain and central nervous system (CNS), breast, colon, liver, lung, mouth and pharynx, esophagus, ovary, salivary gland, small intestine, stomach, and uterus. The lifetime attributed risk (LAR) of cancer induction was estimated using the Schneider et al. excess absolute risk models and dose-volume histograms for the above organs. RESULTS: The sites with the highest LAR estimates were the ipsilateral and contralateral lungs, and contralateral breast for all treatment techniques. For all sites, the LAR estimates for the segmented breast and mammosite treatments were lower than those for the whole breast and APBI treatments. For right-sided target volumes the liver also resulted in high LAR estimates, with all techniques having a LAR greater than 20 per 10 000 person-years (PY), except for mammosite with a mean LAR estimate of 13.2 per 10 000 PY. For left-sided target volumes the stomach also resulted in high LAR estimates, with both whole breast and APBI having a LAR greater than 20 per 10 000 PY, and mammosite the lowest with a LAR of 8.3 per 10 000 PY. CONCLUSION: It is concluded that the lungs and contralateral breast showed high LAR estimates.

Long-term quality-of-life outcomes following treatment for adult obstructive sleep apnoea: comparison of upper airway surgery, continuous positive airway pressure and mandibular advancement splints.

OBJECTIVE: Long-term quality-of-life (QOL) outcomes, complications and clinical effectiveness in patients undergoing treatment with upper airway surgery (UAS), continuous positive airway pressure (CPAP) and mandibular advancement splints (MAS) for adult obstructive sleep apnoea (OSA). DESIGN: Retrospective cohort study. SETTING: Multidisciplinary OSA clinic in University teaching hospital. PARTICIPANTS: Consecutive, simultaneously treated patients with OSA undergoing UAS (n = 83), CPAP (n = 83) and MAS (n = 79). MAIN OUTCOME MEASURES: Glasgow Benefit Inventory (GBI), Snoring Severity Scale (SSS), Epworth Sleepiness Score (ESS) and side-effects in all three groups were recorded at a mean of 34.5 months following start of treatment and compared via anova with Bonferroni's adjustment for pairwise comparisons. RESULTS: Upper airway surgery demonstrated a statistically significant QOL benefit over MAS. All three groups showed a significant improvement in SSS with CPAP significantly better than MAS, but equivalent to UAS. Uncomplicated UAS provided a greater QOL outcome than compliant MAS, non-compliant CPAP (P < 0.05) and comparable to compliant CPAP. Patients undergoing UAS with recorded complications still reported equivalent QOL outcomes to compliant CPAP and MAS, suggesting these surgical complications are relatively minor compared to the QOL benefit of OSA treatment. CONCLUSION: Upper airway surgery showed a significant improvement in QOL outcomes compared to non-compliant CPAP or MAS and equivalent benefit to compliant CPAP. This study strongly supports the role for contemporary UAS in OSA when CPAP is not or no longer an option.

Perception of risk factors and DXA T score among at-risk females of osteoporosis.

AIM: This paper reports a study to investigate the relationships among bone mineral density, demographics, knowledge of osteoporosis, beliefs concerning osteoporosis and preventive behaviours of at-risk females with family histories of osteoporosis. BACKGROUND: Strong evidence demonstrates that genetics is a significant determinant of peak bone mass, with a heritability of 50-90%. However, few studies have examined the bone mineral density of at-risk females with family histories of osteoporosis, particularly in an Asian population. DESIGN: Telephone survey. METHODS: The study population (n=2890) was recruited from a radiology department at a national university medical centre in northern Taiwan during 2005-2006. In total, 886 females completed a questionnaire via the telephone; the participation rate was 30·7%. RESULTS: The bone mineral density of at-risk females was close to osteopenia status (T score of -1 to -2·49). Most subjects were aware of osteoporosis-related information; however, few clearly understood osteoporosis. Furthermore, subjects reported difficult implementing strategies to improve bone mineral density. Variation in bone mineral density was correlated with self-rated health (r=0·56, p<0·05), knowledge of osteoporosis (r=0·66, p<0·05) and preventive behaviours (r=0·68, p<0·05). CONCLUSIONS: This study is to examine risk factors associated with bone mineral density of females with family histories of osteoporosis. Early identification of risk factors for osteoporosis and development of prevention programmes are required to halt the increasing in the incidence of osteoporosis and improve the bone mineral density of at-risk females. RELEVANCE TO CLINICAL PRACTICE: Nursing care professionals, who emphasise primary, secondary and tertiary prevention with individuals and families, should develop effective prevention strategies for women with family the history of osteoporosis to protect the health of these vulnerable populations at-risk for osteoporosis.

Diagnosis of virus infection in orchid plants with high-resolution optical coherence tomography.

This work investigates the use of optical coherence tomography (OCT) to identify virus infection in orchid plants. Besides revealing the cross-sectional structure of orchid leaves, highly scattering upper leaf epidermides are detected with OCT for virus-infected plants. This distinct feature is not observable under histological examination of the leaf samples. Furthermore, the leaf epidermides of stressed but healthy plants, which exhibit similar visual symptoms as virus-infected plants, are not highly scattering and are similar to those of healthy plants. The results suggest that virus-infected orchid plants can be accurately identified by imaging the epidermal layers of their leaves with OCT. The OCT modality is suitable for fast, nondestructive diagnosis of orchid virus infection, which may potentially lead to significant cost savings and better control of the spread of viruses in the orchid industry.

Entamoeba invadens myositis in a common water monitor lizard (Varanus salvator).

Amoebiasis is one of the most common protozoal diseases of reptiles, but amoebic myositis has not been reported in any animal species. An 11-year-old, male common water monitor lizard (Varanus salvator) was found dead with several subacute ulcerated skin wounds. Gross examination revealed multiple discrete to coalescing, white-yellow to gray, caseous foci scattered in the skeletal muscles and liver. The mucosa of small intestine was thickened, red, and contained many variably sized, dark red ulcers, with depressed and hemorrhagic centers. Histopathologic examination revealed severe necrotizing and granulomatous myositis, hepatitis, and enteritis accompanied by large numbers of intralesional, 10-20-microm diameter, periodic acid-Schiff-positive, amoeboid protozoa. Gene sequence analysis of a 136-bp region of the 18S ribosomal RNA amplified by polymerase chain reaction revealed 98-100% similarity with Entamoeba invadens. Aside from intestinal and hepatic involvement, no other internal organs were affected. The muscular infection by E. invadens likely resulted from a combination of direct invasion of trophozoites via skin wounds and hematogenous spread.

Pustular pyoderma gangrenosum: an uncommon variant which is easily misdiagnosed.

Pustular pyoderma gangrenosum is a relatively uncommon clinical form of pyoderma gangrenosum; it presents with vesiculo-pustular lesions that do not develop into frank ulceration. We report a case of a 44-year-old man with associated ulcerative colitis, who was misdiagnosed as having necrotizing fasciitis. He underwent multiple debridements and a subsequent skin grafting procedure, but without improvement. The diagnosis of pyoderma gangrenosum is often challenging because there is no defining diagnostic clinical, laboratory, or histopathological feature. A high index of suspicion is, therefore, essential to diagnose pyoderma gangrenosum clinically because failure to do so in the early stages of the disease can lead to disfigurement and even unnecessary and detrimental surgery.

Phrynoderma: a forgotten entity in a developed country.

Phrynoderma is a type of follicular hyperkeratosis attributed to various nutritional deficiencies, most notably vitamin A. We report a case of a 31-year-old mentally-deficient man who was a resident of a voluntary welfare nursing home. He presented with characteristic hyperkeratotic follicular papules on his trunk in a setting of low serum level of vitamin A and malnutrition. Although commonly seen in South and East Asia, it is rarely reported in Singapore. However, there is still a population at risk here--patients with malabsorption and eating disorders, and institutionalised persons. Phrynoderma should, therefore, be considered in the differential diagnosis in patients with hyperkeratotic folliculitis, especially when malnutrition is also present.

Clinical significance of intrasubstance meniscal lesions on MRI.

Grade 2 meniscal changes on MRI are linear signals confined within the meniscus thought to represent areas of meniscal degeneration or intrasubstance tears. It has been reported that in only 10% of cases is a meniscal tear detected during subsequent arthroscopy. Usually non-operative management is appropriate, but in some cases, grade 2 meniscal changes are seen on MRI in patients with a typical presentation of a meniscal tear. In this circumstance, an arthroscopic partial meniscectomy may be indicated and an MRI report, which describes the meniscus as being normal, may be confusing. A pilot study of 10 consecutive symptomatic patients (mean age 28.1 years) with a grade 2 meniscal signal on MRI was performed. At arthroscopy, with thorough examination of the meniscus using a probe, an intrasubstance tear was detected in all 10 patients. Partial meniscectomy was performed, with a mean follow-up of 6.7 months. All but one patient (due to other pathology) had marked improvement in pain and function. Thus, the authors believe that grade 2 signal changes should be reported in a manner that raises the possibility that they may cause symptoms and that the presence of any intrasubstance changes should be clearly conveyed in the report.