Whole-exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways.

BACKGROUND: Through whole-exome sequencing of 60 formalin-fixed paraffin-embedded Nigerian (NGRn) benign prostatic hyperplasia (BPH) samples, we identified germline and somatic alterations in apoptotic pathways impacting BPH development and progression. Prostate enlargement is a common occurrence in male aging; however, this enlargement can lead to lower urinary tract symptoms that negatively impact quality of life. This impact is disproportionately present in men of African ancestry. BPH pathophysiology is poorly understood and studies examining non-European populations are lacking. METHODS: In this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH. RESULTS: Two hundred and two nonbenign, ClinVar-annotated germline variants were present in NGRn BPH samples. Six genes [BRCA1 (92%), HSD3B1 (85%), TP53 (37%), PMS2 (23%), BARD1 (20%), and BRCA2 (17%)] were altered in at least 10% of samples; however, compared to NGRn normal and tumor, the frequency of alterations in BPH samples showed no significant differences at the gene or variant level. BRCA2_rs11571831 and TP53_rs1042522 germline alterations had a statistically significant co-occurrence interaction in BPH samples. In at least two BPH samples, 173 genes harbored somatic variants known to be clinically actionable. Three genes (COL18A1, KIF16B, and LRP1) showed a statistically significant (p < 0.05) higher frequency in BPH. NGRn BPH also had five gene pairs (PKD1/KIAA0100, PKHD1/PKD1, DNAH9/LRP1B, NWD1/DCHS2, and TCERG1/LMTK2) with statistically significant co-occurring interactions. Two hundred and seventy-nine genes contained novel somatic variants in NGRn BPH. Three genes (CABP1, FKBP1C, and RP11-595B24.2) had a statistically significant (p < 0.05) higher alteration frequency in NGRn BPH and three were significantly higher in NGRn tumor (CACNA1A, DMKN, and CACNA2D2). Pairwise Fisher's exact tests showed 14 gene pairs with statistically significant (p < 0.05) interactions and four interactions approaching significance (p < 0.10). Mutational patterns in NGRn BPH were similar to COSMIC (Catalog of Somatic Mutations in Cancer) signatures associated with aging and dysfunctional DNA damage repair. CONCLUSIONS: NGRn BPH contained significant germline alteration interactions (BRCA2_rs11571831 and TP53_rs1042522) and increased somatic alteration frequencies (LMTK2, LRP1, COL18A1, CABP1, and FKBP1C) that impact apoptosis. Normal prostate development is maintained by balancing apoptotic and proliferative activity. Dysfunction in either mechanism can lead to abnormal prostate growth. This work is the first to examine genomic sequencing in NGRn BPH and provides data that fill known gaps in the understanding BPH and how it impacts men of African ancestry.

Prevalence and Risk Factors of Genital Human Papillomavirus Infections among Women in Lagos, Nigeria.

Regional variations exist in HPV prevalence worldwide despite reports of high prevalence rates among African women. Limited data on genital HPV prevalence necessitated this study with the aim of determining the prevalence of genital HPV and associated risk factors among women in Lagos, Nigeria. Exfoliated cervical cells were collected with consent from 165 women using a cervical brush. Viral DNA was extracted and amplified by nested PCR using two sets of consensus primers (MY09/11 and GP5+/6+). An unconditional logistic regression model was used to identify predictors of HPV positivity. The HPV prevalence was 81.82% in all women and 87.59% in women with normal cytology. The risk of HPV infection was significantly increased among women who had a history of STI (odds ratio (OR) 3.94; 95% confidence interval (CI): 1.51-10.25, p = 0.005) while there was a significantly reduced risk of HPV infection among those who used condoms (odds ratio (OR) 3.94; 95% confidence interval (CI): 0.18-0.91, p = 0.03). The HPV prevalence observed shows an increased transmission of the virus in Lagos, Nigeria. Therefore, there is a need for intense public awareness and the implementation of early detection tests, treatment, and vaccination to prevent an increase in cervical cancer cases in Lagos, Nigeria.

Whole-exome Sequencing of Nigerian Prostate Tumors from the Prostate Cancer Transatlantic Consortium (CaPTC) Reveals DNA Repair Genes Associated with African Ancestry.

In this study, we used whole-exome sequencing of a cohort of 45 advanced-stage, treatment-naïve Nigerian (NG) primary prostate cancer tumors and 11 unmatched nontumor tissues to compare genomic mutations with African American (AA) and European American (EA) The Cancer Genome Atlas (TCGA) prostate cancer. NG samples were collected from six sites in central and southwest Nigeria. After whole-exome sequencing, samples were processed using GATK best practices. BRCA1 (100%), BARD1 (45%), BRCA2 (27%), and PMS2(18%) had germline alterations in at least two NG nontumor samples. Across 111 germline variants, the AA cohort reflected a pattern [BRCA1 (68%), BARD1 (34%), BRCA2 (28%), and PMS2 (16%)] similar to NG samples. Of the most frequently mutated genes, BRCA1 showed a statistically (P ≤ 0.05) higher germline mutation frequency in men of African ancestry (MAA) and increasing variant frequency with increased African ancestry. Disaggregating gene-level mutation frequencies by variants revealed both ancestry-linked and NG-specific germline variant patterns. Driven by rs799917 (T>C), BRCA1 showed an increasing mutation frequency as African ancestry increased. BRCA2_rs11571831 was present only in MAA, and BRCA2_rs766173 was elevated in NG men. A total of 133 somatic variants were present in 26 prostate cancer-associated genes within the NG tumor cohort. BRCA2 (27%), APC (20%), ATM (20%), BRCA1 (13%), DNAJC6 (13%), EGFR (13%), MAD1L1 (13%), MLH1 (11%), and PMS2 (11%) showed mutation frequencies >10%. Compared with TCGA cohorts, NG tumors showed statistically significant elevated frequencies of BRCA2, APC, and BRCA1. The NG cohort variant pattern shared similarities (cosign similarities ≥0.734) with Catalogue of Somatic Mutations in Cancer signatures 5 and 6, and mutated genes showed significant (q < 0.001) gene ontology (GO) and functional enrichment in mismatch repair and non-homologous repair deficiency pathways. Here, we showed that mutations in DNA damage response genes were higher in NG prostate cancer samples and that a portion of those mutations correlate with African ancestry. Moreover, we identified variants of unknown significance that may contribute to population-specific routes of tumorigenesis and treatment. These results present the most comprehensive characterization of the NG prostate cancer exome to date and highlight the need to increase diversity of study populations. Significance: MAA have higher rates of prostate cancer incidence and mortality, however, are severely underrepresented in genomic studies. This is the first study utilizing whole-exome sequencing in NG men to identify West African ancestry-linked variant patterns that impact DNA damage repair pathways.

The Simple Triage Scoring System (STSS) successfully predicts mortality and critical care resource utilization in H1N1 pandemic flu: a retrospective analysis.

INTRODUCTION: Triage protocols are only initiated when it is apparent that resource deficits will occur across a broad geographical area despite efforts to expand or acquire additional capacity. Prior to the pandemic the UK Department of Health (DOH) recommended the use of a staged triage plan incorporating Sepsis-related Organ Failure Assessment (SOFA) developed by the Ontario Ministry of Health to assist in the triage of critical care admissions and discharges during an influenza outbreak in the UK. There are data to suggest that had it been used in the recent H1N1 pandemic it may have led to inappropriate limitation of therapy if surge capacity had been overwhelmed. METHODS: We retrospectively reviewed the performance of the Simple Triage Scoring System (STSS) as an indicator of the utilization of hospital resources in adult patients with confirmed H1N1 admitted to a university teaching hospital. Our aim was to compare it against the staged initial SOFA score process with regards to mortality, need for intensive care admission and requirement for mechanical ventilation and assess its validity. RESULTS: Over an 8 month period, 62 patients with confirmed H1N1 were admitted. Forty (65%) had documented comorbidities and 27 (44%) had pneumonic changes on their admission CXR. Nineteen (31%) were admitted to the intensive care unit where 5 (26%) required mechanical ventilation (MV). There were 3 deaths. The STSS group categorization demonstrated a better discriminating accuracy in predicting critical care resource usage with a receiver operating characteristic area under the curve (95% confidence interval) for ICU admission of 0.88 (0.78-0.98) and need for MV of 0.91 (0.83-0.99). This compared to the staged SOFA score of 0.77 (0.65-0.89) and 0.87 (0.72-1.00) respectively. Low mortality rates limited analysis on survival predictions. CONCLUSIONS: The STSS accurately risk stratified patients in this cohort according to their risk of death and predicted the likelihood of admission to critical care and the requirement for MV. Its single point in time, accuracy and easily collected component variables commend it as an alternative reproducible system to facilitate the triage and treatment of patients in any future influenza pandemic.

From a small local audit to a regional quality improvement project - Improving lung protective ventilation.

BACKGROUND: Lung protective ventilation with tidal volumes (VT) of 6-8 ml per kg ideal body weight have been shown to reduce mortality in patients with acute respiratory distress syndrome and reduce post-operative pulmonary complications in major abdominal surgery. Following a local audit on weight recording, the Southcoast Perioperative Audit and Research Collaboration (SPARC) conducted a regional multi-disciplinary survey on the current practice in lung protective ventilation in the Wessex region. This resulted in a quality improvement project improving lung protective ventilation across these intensive care units. METHODS: Over one-week period in January over two consecutive years, lung protective ventilation parameters of mandatory ventilated patients (above the age of 18 years) were audited in intensive care units in the Wessex region. RESULTS: A total 1843 hours of mandatory ventilation were audited. The quality improvement project led to an improvement of lung protective ventilation with an average of 30% higher duration of ventilation with VT < 8 ml/kg ideal body weight. There was a suggestion that documentation of height and weight on admission to intensive care units improved compliance with lung protective ventilation. CONCLUSIONS: Adherence to lung protective ventilation is variable across intensive care units but can be improved by recording patient's weight and height accurately and using simple chart to help calculate the appropriate tidal volume. Additionally, this project demonstrates how a regional audit and quality improvement network can help to facilitate regional quality improvement.

Pathology Services in Nigeria: Cross-Sectional Survey Results From Three Cancer Consortia.

PURPOSE: Cancer incidence is increasing in sub-Saharan Africa, yet there is little information on the capacity of pathology laboratories in this region. We aimed to assess the current state of pathology services in Nigeria to guide strategies to ensure best practices and improve the quality of surgical specimen handling. METHODS: We developed structured pathology survey to assess tissue handling, sample processing, and immunohistochemistry (IHC) capabilities. The survey was distributed electronically to 22 medical centers in Nigeria that are part of established cancer consortia. Data were collected between September and October 2017. RESULTS: Sixteen of 22 centers completed the survey in full. All 16 institutions had at least one board-certified pathologist and at least one full-time laboratory scientist/technologist. The majority of responding institutions (75%) reported processing fewer than 3,000 samples per year. For sample processing, 38% of institutions reported manual tissue processing and 75% processed biopsies and surgical specimens together. The average tissue fixation time ranged from 5 to more than 72 hours before processing and paraffin embedding. Half of the institutions reported having no quality assurance processes to evaluate hematoxylin and eosin-stained slides, and 25% reported having no written operating procedures. Half of the participating institutions have a facility for routine IHC staining, and among these there was considerable variability in processes and validation procedures. External proficiency testing was not common among surveyed sites (38%). CONCLUSION: Data from 16 Nigerian medical institutions indicate deficiencies in standardization, quality control, and IHC validation that could affect the reliability of pathology results. These findings highlight addressable gaps in pathology services that can ensure accurate diagnosis and follow-up for the growing number of patients with cancer in this region.

Exploring the Waveform Characteristics of Tidal Breathing Carbon Dioxide, Measured Using the N-Tidal C Device in Different Breathing Conditions (The General Breathing Record Study): Protocol for an Observational, Longitudinal Study.

BACKGROUND: In an increasingly comorbid population, there are significant challenges to diagnosing the cause of breathlessness, and once diagnosed, considerable difficulty in detecting deterioration early enough to provide effective intervention. The burden of the breathless patient on the health care economy is substantial, with asthma, chronic heart failure, and pneumonia affecting over 6 million people in the United Kingdom alone. Furthermore, these patients often have more than one contributory factor to their breathlessness symptoms, with conditions such as dysfunctional breathing pattern disorders-an under-recognized component. Current methods of diagnosing and monitoring breathless conditions can be extensive and difficult to perform. As a consequence, home monitoring is poorly complied with. In contrast, capnography (the measurement of tidal breath carbon dioxide) is performed during normal breathing. There is a need for a simple, easy-to-use, personal device that can aid in the diagnosis and monitoring of respiratory and cardiac causes of breathlessness. OBJECTIVE: The aim of this study was to explore the use of a new, handheld capnometer (called the N-Tidal C) in different conditions that cause breathlessness. We will study whether the tidal breath carbon dioxide (TBCO2) waveform, as measured by the N-Tidal C, has different characteristics in a range of respiratory and cardiac conditions. METHODS: We will perform a longitudinal, observational study of the TBCO2 waveform (capnogram) as measured by the N-Tidal C capnometer. Participants with a confirmed diagnosis of asthma, breathing pattern disorders, chronic heart failure, motor neurone disease, pneumonia, as well as volunteers with no history of lung disease will be asked to provide twice daily, 75-second TBCO2 collection via the N-Tidal C device for 6 months duration. The collated capnograms will be correlated with the underlying diagnosis and disease state (stable or exacerbation) to determine if there are different TBCO2 characteristics that can distinguish different respiratory and cardiac causes of breathlessness. RESULTS: This study's recruitment is ongoing. It is anticipated that the results will be available in late 2018. CONCLUSIONS: The General Breathing Record Study will provide an evaluation of the use of capnography as a diagnostic and home-monitoring tool for various diseases. REGISTERED REPORT IDENTIFIER: RR1-10.2196/9767.

Malignant melanoma in a black child: predisposing precursors and management.

Malignant melanoma (MM) remains a pediatric rarity world-wide, but perhaps more so in black Africans. To the best of our knowledge, the current report of MM in a two-and-a-half-year-old Nigerian who had a pre-existing congenital giant hairy nevus is probably the first (in an accessible literature) in a black African child. Primary neoplastic transformation and metastatic spread were suggested by the appearance of multiple swellings over the "garment" precursor nevus at the posterior trunk, multiple ipsilateral axillary nodal enlargement, and fresh occipital swellings postadmission. Smaller-sized hyperpigmented lesions with irregular, nonlobulated, and frequently hairy surfaces were also discernible over the upper and lower extremities, but the face, anterior trunk, and mucosal surfaces were relatively spared. A diagnosis of MM was confirmed by the subsequent histopathologic findings from the fine-needle aspirate and biopsy specimens. Chemotherapy was initiated but was truncated shortly after by parent-pressured discharge. Despite the rarity of MM in a tropical African setting where management options are few, the current case underscores the need for a high clinical index of diagnostic suspicion, an early pursuit of investigative confirmation, and prophylactic excision in children with the predisposing skin lesions, like congenital giant hairy nevus. An expounded discourse of the possible precursors and management options of MM is provided. We emphasize the need for institutional cost subsidy for anticancer care in tropical children.

Socio-demographic and clinical profile of immuno-histochemically confirmed breast cancer in a resource limited country.

INTRODUCTION: Breast cancer is the most common cancer in females. It is the most common cause of cancer-related death among women with fatality rates highest in low-income countries. The aim of this study is to determine the socio-demographic and clinical profile of patients with immunohistochemically confirmed breast cancer in a Nigerian tertiary health institution. METHODS: Patients with immunohistochemically confirmed breast cancer were reviewed. The information retrieved was entered into a proforma designed for the purpose of the study. Data was analysed using SPSS version 18.0. RESULTS: The peak incidence of age at presentation was in the 5th decade. More than 50% of the patients were premenopausal and perimenopausal at presentation. Only 11% of the patients presented with breast lumps less than 2 cm in size. Women in the age group 50-59 years are more likely to present with larger breast lumps than women in other groups. More than 50% had clinically palpable lymph node at presentation. Mastectomy (simple mastectomy and modified radical mastectomy) and adjuvant chemotherapy were the main form of treatment. Most of the cases were estrogen receptor negative with majority of them having basal-like subtype. CONCLUSION: Most of the patients in this study were not only young but presented with locally advanced disease. Population screening, adequate health education, improved accessibility and availability of heath care will go a long way to improve the outcome of these patients.

Symptom score for allergic rhinitis.

OBJECTIVES: To determine the prevalence of allergic rhinitis in our study population and the correlation between the Score for Allergic Rhinitis (SFAR) and nasal smear eosinophil count. STUDY DESIGN: Cross-sectional study. SETTING: Ear, nose, and throat clinic, University of Ilorin Teaching Hospital, Nigeria; a 450-bed tertiary health facility. SUBJECTS: Two hundred seventy-five consecutive, consenting patients who presented with nasal symptoms. METHODS: Information on the 8-parameter symptom score was collected using a semistructured questionnaire by interview. Nasal smear slides were air dried, fixed with 95% alcohol, stained using May-Grünwald-Giemsa stain, and examined under a light microscope. RESULTS: Of the 275 participants seen during the 1-year study, 116 (42.2%) were males. The mean ± SD age was 38.5 ± 16.3 (range, 14-75) years. Eighty-one (29.5%) were diagnosed with allergic rhinitis using a nasal smear eosinophil count. The most common symptom was excessive sneezing, involving 93% of patients with allergic rhinitis (P < .001). The prevalence of allergic rhinitis using SFAR was 31.6%. The SFAR cutoff was set at >8 (P < .001). The sensitivity and specificity for SFAR were 94.8% (confidence interval [CI], 90.5%-97.4%) and 95.1% (CI, 87.2%-98.4%), respectively. A high Spearman's correlation (0.88) was obtained for SFAR when correlated with nasal smear eosinophil count. CONCLUSION: The prevalence of allergic rhinitis using SFAR was 31.6%. The study shows that SFAR can be used as a simple, valid diagnostic tool in allergic rhinitis. This is important in rural settings where access to laboratory investigations might not be readily available.

The pathophysiology of perioperative lung injury.

The degree of perioperative lung injury that patients sustain results from a complex interaction between their current physiologic state, comorbidities, lifestyle choices, underlying surgical diagnosis, operative, and ultimately their cardiopulmonary interaction with a mechanical ventilator. This review addresses primarily the pathophysiology of perioperative lung injury with reference to ventilator-induced lung injury and acute respiratory distress syndrome.