A multicentre review of the direct-access mammography programme in Ireland for women with breast pain.

AIM: To assess the current use of the direct access mammography pathway for breast pain and the rate of breast cancer detection in this patient cohort. MATERIALS AND METHODS: A retrospective review of general practitioner (GP)-referred mammograms performed during a 12-month period from January to December 2022 across four tertiary referral centres. With the use of medical records and GP referrals, patient demographics, presenting symptoms, family history, and clinical outcomes were recorded. RESULTS: The present study comprised 2,046 patients of which 21.6% did not report breast pain at the time of referral. Thirty-five per cent had a positive family history with 40% of these patients having no breast pain. Twelve per cent were recalled with 30% of these patients requiring biopsy. An overall cancer detection rate (CDR) of 7 per 1000 was determined for women with mastalgia. A CDR of 0 per 1,000 was determined for women <50 years with mastalgia alone and no additional risk factors for malignancy. Fisher's exact test showed no statistically significant association between breast pain and breast cancer. CONCLUSION: There was no statistically significant relationship found between breast pain and breast cancer. This review suggests a low cancer detection rate in women <50 years. In women <50 years with mastalgia without additional symptoms or family history, breast imaging is not required.

There is more to this fever than meets the eye: A case of neuroleptic malignant-like syndrome (NMLS) secondary to withdrawal of procyclidine and L-dopa on a background of long-standing flupenthixol depot use.

This case report highlights the risk of development of Neuroleptic Malignant-Like Syndrome secondary to withdrawal of procyclidine with brief withdrawal of L-dopa and long-term typical antipsychotic depot. The patient responded to reintroduction of procyclidine, sedation and supportive treatment. The mechanism and management of NMS and NMLS is also reviewed. This case emphasises that any changes in antipsychotic and antiparkinsonian medications should be undertaken with extreme caution and patient should be closely monitored for development of NMLS after alteration in these medications.

Approach to the Management of Hypernatraemia in Older Hospitalised Patients.

Hypernatraemia is associated with high morbidity and mortality and is more common in patients of older age, nursing home residents and those with cognitive impairment and restricted mobility. The most common cause in hospital settings is water dehydration due to reduced intake although other causes should be identified. Once identified, prompt management is necessary to avoid delayed correction as prolonged hypernatremia is associated with increased hospital stay and mortality. Comprehensive history-taking and physical examination, basic investigations and medication review are essential to identify causative and remediable factors in those admitted with hypernatraemia. Accurate calculation of fluid deficit and ongoing losses is essential in order to ensure adequate fluid replacement, The administration of appropriate, usually hypotonic, fluids is also essential to the timely restoration of eunatraemia. Although evidence of definite harm resulting from rapid correction is lacking, a serum sodium reduction rate of <12 mmol/l day is advised with the caveat that close monitoring of electrolytes is required to ensure the desired correction rate is being achieved. Medical and nursing professionals should have access to a local hospital protocol to guide management of patients with hypernatraemia to improve patient outcomes and mitigate the risk of harm, particularly from under-recognition and slow correction.

Optical fibre based real-time measurements during an LDR prostate brachytherapy implant simulation: using a 3D printed anthropomorphic phantom.

An optical fibre sensor based on radioluminescence, using the scintillation material terbium doped gadolinium oxysulphide (Gd2O2S:Tb) is evaluated, using a 3D printed anthropomorphic phantom for applications in low dose-rate (LDR) prostate brachytherapy. The scintillation material is embedded in a 700 µm diameter cavity within a 1 mm plastic optical fibre that is fixed within a brachytherapy needle. The high spatial resolution dosimeter is used to measure the dose contribution from Iodine-125 (I-125) seeds. Initially, the effects of sterilisation on the sensors (1) repeatability, (2) response as a function of angle, and (3) response as a function of distance, are evaluated in a custom polymethyl methacrylate phantom. Results obtained in this study demonstrate that the output response of the sensor, pre- and post-sterilisation are within the acceptable measurement uncertainty ranging from a maximum standard deviation of 4.7% pre and 5.5% post respectively, indicating that the low temperature sterilisation process does not damage the sensor or reduce performance. Subsequently, an LDR brachytherapy plan reconstructed using the VariSeed treatment planning system, in an anthropomorphic 3D printed training phantom, was used to assess the suitability of the sensor for applications in LDR brachytherapy. This phantom was printed based on patient anatomy, with the volume and dimensions of the prostate designed to represent that of the patient. I-125 brachytherapy seeds, with an average activity of 0.410 mCi, were implanted into the prostate phantom under trans-rectal ultrasound guidance; following the same techniques as employed in clinical practice by an experienced radiation oncologist. This work has demonstrated that this sensor is capable of accurately identifying when radioactive I-125 sources are introduced into the prostate via a brachytherapy needle.

A catalog of associations between rare coding variants and COVID-19 outcomes.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable at https://rgc-covid19.regeneron.com.

Establishing Benefit from Vitamin D Supplementation - Adherence to Defined Criteria and Targeting of High-Risk Groups Essential?

BACKGROUND: Vitamin D is the one of the most common nutritional deficiencies worldwide, and insufficiency or deficiency can be associated with musculoskeletal and non-skeletal conditions such as cancer, cardiovascular disease and diabetes mellitus. OBJECTIVE: Recent data suggests that Vitamin D is relatively safe and toxicity is rarer than previously indicated. However, international guidelines regarding dosage and target plasma levels are conflicting. Moreover multiple well-designed studies of healthy older adults, unselected in terms of Vitamin D status, have revealed largely negative results (with the possible exception of older patients in care homes/hospitals) in terms of improvement in musculoskeletal and non-skeletal conditions to date. CONCLUSION: On that basis, it is suggested that future trials regarding Vitamin D supplementation should be carried out in high-risk groups. The use of published criteria for evaluating the effect of nutrients and targeting of individuals with Vitamin D insufficiency and deficiency for inclusion in such studies is also proposed. The identification of specific subgroups that will benefit from supplementation and replacement, and the establishment of a scientific basis for such therapy, should be possible with this approach.

Optical fiber dosimeter for real-time in-vivo dose monitoring during LDR brachytherapy.

An optical fiber sensor for monitoring low dose radiation is presented. The sensor, based on radiation sensitive scintillation material, terbium doped gadolinium oxysulphide (Gd2O2S:Tb), is embedded in a cavity of 700µm diameter within a 1mm plastic optical fiber. The sensor is compared with the treatment planning system for repeatability, angular dependency, distance and accumulated radiation activity. The sensor demonstrates a high sensitivity of 152 photon counts/Gy with a temporal resolution of 0.1 seconds, with the largest repeatability error of 4.1%, to 0.361mCi of Iodine-125 the radioactive source most commonly used in LDR brachytherapy for treating prostate cancer.

Comparison of the utility of clinical breast examination and MRI in the surveillance of women with a high risk of breast cancer.

AIM: To review surveillance magnetic resonance imaging (MRI) and clinical breast examinations (CBE) performed for women at high risk of breast cancer in order to determine recall and cancer-detection rates. MATERIALS AND METHODS: Data were collected on all surveillance MRI examinations performed at St James's Hospital in 2016 for women at high risk of developing breast cancer. Data collected included age, indication for MRI, MRI score, ultrasound indications and scores, and histology findings. Ultrasound scores were recorded from CBEs that received a score of ≥3. RESULTS: A total of 385 breast surveillance MRI examinations and CBEs were performed for women at high risk of breast cancer. A recall rate of 11.2% was documented for breast MRI examinations, whereas a recall rate of 6.2% was identified for CBEs. The biopsy rate was 6.2% for MRI and 0.2% for CBE. The cancer detection rate was 1.6% or 16 per 1,000 for MRI screening and 0% for CBE. CONCLUSION: The high cancer detection rate in the present study supports the unparalleled sensitivity of breast MRI surveillance. Furthermore, the present study did not identify any breast cancers through CBE, suggesting it is not a critical component of the surveillance programme of high-risk women. The current UK guidelines recommending a target recall rate of 7% were not met in the present study or by other studies in the literature, collectively suggesting the guidelines may not be reflective of what is attainable in clinical practice.

Fulminant Skeletal Failure in a Centenarian: The Impact of Nutrition and Immobility.

This case describes a 103-year-old lady who presented from home with an incidental diagnosis of a left femoral fracture. She had no history of trauma and denied pain. She had a known diagnosis of osteoporosis, and sustained a fracture of the contralateral femur aged 93 which was managed conservatively. She was bed-bound with fixed contractures, poor oral intake and was non-compliant with prescribed calcium/vitamin D supplementation. Clinical biochemical measurements showed severe vitamin D deficiency and mild hypocalcaemia. Secondary hyperparathyroidism in the setting of an inappropriately normal phosphate suggested concurrent renal bone disease. Biomarkers of bone turnover were also consistent with bone remodelling. The history of prior fragility fractures, severe vitamin D deficiency and immobility supports a diagnosis of osteoporotic fracture, however other causes of spontaneous fracture were also considered. This case highlights the complexity of interpreting clinical biochemistry results in the setting of multi-morbidity and addresses the challenges of bone health management in the frail older person.

Spontaneous Insufficiency Fractures.

Spontaneous insufficiency fractures are caused by normal or physiological stress on weakened bone. The leading cause of insufficiency fractures is osteoporosis which has a propensity to affect older patients. Other causes or associated factors are disorders which affect bone metabolism, collagen formation, bone remodelling and medications such as bisphosphonates and glucocorticoids. Pathological fractures and abuse are important causes of unexplained fractures which warrant careful consideration. Spontaneous fractures of the long bones affect on average 1% of nursing home residents per year and tend to occur in patients who are bed-bound with joint contractures. Preventative measures for spontaneous insufficiency fractures include optimising nutrition to include an adequate intake of protein, calcium and vitamin D, maintaining mobility and preventing long periods of bed-rest and treatment of underlying pre-disposing conditions.

A review of vitamin D insufficiency and its management: a lack of evidence and consensus persists.

Vitamin D deficiency is the most common nutritional deficiency worldwide, however uncertainty persists regarding the benefits of vitamin D supplementation. Vitamin D is essential for calcium homeostasis, and has been linked to falls and fractures in older people. There are numerous risk factors for vitamin D deficiency, chief among them old age. Studies of vitamin D supplementation have given mixed signals, but over all there is evidence of benefit for those with risk factors for deficiency. International guidelines recommend vitamin D target levels of >25 to >80 nmol/l, best achieved by a daily dose of 800-1000 IU. Large bolus doses should be avoided. There are still unanswered questions regarding vitamin D supplementation and target levels. There is need for well designed and powered trials to achieve consensus.

Vitamin D Deficiency and Insufficiency Prevalence in the West of Ireland - A Retrospective Study.

OBJECTIVES: Vitamin D plays an important role in calcium homeostasis and is essential for normal bone growth and remodeling. Previous studies of acutely ill and institutionalized older women in Galway revealed that vitamin D insufficiency is extremely common. We aimed to evaluate age and gender-related rates of vitamin D insufficiency and deficiency in adult patients attending their General Practitioners in the same region. DESIGN: A retrospective cohort study. SETTING: General practices in Galway, a city located on the west coast of Ireland, latitude 53.17 North. PARTICIPANTS: A total of 15,708 consecutive blood samples from adults attending their General Practitioners between January 2013 and December 2014 were sent to the Clinical Biochemistry Laboratory in the University Hospital Galway for vitamin D level testing. 73% were from women. INTERVENTION: Data were collected and grouped according to age, sex and season. Vitamin D levels (25OHD) were categorised into deficiency (<25nmol/L), insufficiency (25-50nmol/L) and sufficiency ( >50nmol/L). MEASUREMENTS: Median and interquartile range were reported as vitamin D levels were not normally distributed. Descriptive statistics were performed using STATA/MP 13.1 for Mac. RESULTS: While vitamin D levels were sufficient in 56.4% (n=8,496), they were insufficient in 32.4% (n=4,891) and deficient in 11.2% (n=1,691). Of the deficient group, 19%( 325) had levels <15nmol/L consistent with profound deficiency. Men were more likely than women to be deficient (12% (n=489) vs. 10.9% (n=1,202)) and insufficient (38.0% (n=1,550) vs. 30.4% (n=3,341)) (p<0.01). Highest rates of deficiency were seen in those 81-97 years (19.4% (n=136)) and 18-40 years (13.8% (n=543)), the former group showing less seasonal variation. CONCLUSION: Overall prevalence of insufficiency is similar to those in national and European studies published recently. However, there is a high possibility that those most vulnerable to vitamin D deficiency were underrepresented in this cohort, when results from previous studies in the same region are considered. Further prospective studies are needed to guide treatment with supplementation of vitamin D for appropriate subgroups.

NF-κB signalling is involved in immune-modulation, but not basal functioning, of the mouse suprachiasmatic circadian clock.

Circadian rhythms are recurring near-24 hour patterns driven by an endogenous circadian timekeeping system. The master pacemaker in this system is the hypothalamic suprachiasmatic nucleus (SCN). Recently interest has been drawn to how the SCN clock responds to immune system stimulation. A major signalling component in the immune system is nuclear factor (NF)-κB. In the present study we examined the role of NF-κB in SCN function. Whilst serum shocked fibroblasts showed rhythmic nuclear localisation of p65 and p65-dependent transcription, there were no circadian changes in the SCN in expression of the NF-κB components p65, c-Rel, p-IκB or p-IKK. Chronic treatment with the NF-κB inhibitor PDTC did not impact on circadian or diurnal rhythms. Phase-shifting light pulses did not impact on SCN expression of p65, and PDTC treatment did not attenuate the behavioural or molecular response to light pulses. Peripheral treatment with lipopolysaccharide resulted in increased NF-κB component expression in the SCN. In vitro experiments with SCN slice cultures showed that treatment with NF-κB inhibitors did not markedly alter rhythmic changes in PER2::LUC expression. Further, SCN slices from nf-κb::luc mice did not show any evidence for circadian rhythms in NF-κB-mediated transcription. Experiments utilising older mice (~16 months old) showed that SCN treatment in vitro with PDTC resulted in increased amplitude of rhythmic PER2::LUC expression, and LPS treatment resulted in altered PER2::LUC rhythm acrophase. Overall, we interpret our results as providing evidence for the involvement of NF-κB in the suprachiasmatic circadian clock following immune stimulation, but not under basal conditions.

Imaging features and diagnosis of tuberculosis of the breast.

AIM: To outline the pathophysiology, clinical presentation, imaging features, and relevant investigations of the different subtypes of breast tuberculosis (TB). MATERIALS AND METHODS: A review was undertaken of all cases (33 in total) of breast TB presenting to Barts Health NHS Trust within a 10-year period, including patient demographics, imaging features, and route of diagnosis. RESULTS: Thirty-three cases of proven granulomatous TB of the breast were identified (11 mastitis obliterans, 10 nodular caseous form, five sclerosing form, four disseminated disease, and three abnormal axillary lymph nodes). No cases of miliary breast TB were identified. Fine-needle aspiration cytology aided diagnosis in six patients (<20% of cases); however, the majority of patients required further investigation; namely core biopsy. Over a third of patients (12/33) had multiple clinic attendances prior to diagnosis. Mean delay in diagnosis was 3.7 months (median 0 months, IQR= 3). CONCLUSION: Breast TB is a rare challenging diagnosis with a wide range of imaging features. Core biopsy is essential for definitive diagnosis. A multidisciplinary approach involving surgeons, radiologists, TB consultants, and microbiologists is required, coupled with a high index of clinical suspicion in order to aid timely diagnosis, and initiate prompt treatment to reduce complications.

The value of routine screening mammography in women aged 35-39 years in a symptomatic breast unit.

AIM: To determine the breast cancer detection rate at routine bilateral screening mammography in women aged 35-39 years attending a symptomatic breast clinic, in women of population-risk profile with a normal clinical examination. METHODS AND MATERIALS: A retrospective analysis of all mammograms performed on patients aged 35-39 years at St James's Hospital from 2011-2015 was carried out. Patients with moderate or high familial risk of breast cancer, personal breast cancer history or chest radiation, males, general practitioner (GP) and internal hospital referrals, and those with abnormal clinical examinations were excluded. Included women had "normal", "benign", or undocumented examination findings. Results of imaging, including ultrasound and histopathological results, were recorded. Information was extracted from the hospital's electronic record systems. RESULTS: Of 4,087 patients aged 35-39 who had bilateral mammograms from 2011-2015, 2,148 patients were excluded from analysis. Of 1,939 included women, four (0.21%) were diagnosed with breast cancer confirmed at histology based on mammographic findings: two invasive ductal carcinoma (8 and 2 mm) and two ductal carcinoma in situ (DCIS; 4.5 mm high-grade DCIS and 2 mm low-grade DCIS). Other histological findings included two B3, 46 B2, and three B1 lesions. Overall, 115 biopsies were performed in this cohort; 55 (47.8%) were attributable to mammographic screening, producing a biopsy rate of 2.8% due to mammography alone. CONCLUSION: Per 1,000 women screened, 2.1 cases of cancer were detected. This figure would be below accepted international thresholds to undertake screening mammography and raises radiation protection issues. Additionally, a large number of benign biopsies were undertaken, with likely resultant psychological impact. Further studies could inform national guidance.

Optical fibre sensors: their role in in vivo dosimetry for prostate cancer radiotherapy.

Review is made of dosimetric studies of current optical fibre technology in radiotherapy for therapeutic applications, focusing particularly on in vivo dosimetry for prostate radiotherapy. We present the various sensor designs along with the main advantages and disadvantages associated with this technology. Optical fibres are ideally placed for applications in radiotherapy dosimetry; due to their small size they are lightweight and immune to electromagnetic interferences. The small dimensions of optical fibres allows it to be easily guided within existing brachytherapy equipment; for example, within the seed implantation needle for direct tumour dose analysis, in the urinary catheter to monitor urethral dose, or within the biopsy needle holder of the transrectal ultrasound probe to monitor rectal wall dose. The article presents the range of optical fibre dosimeter designs along with the main dosimetric properties required for a modern in vivo dosimetry system to be utilised in a clinical environment.