The association between empathy and burnout in medical students: a systematic review and meta-analysis.

BACKGROUND: Burnout levels in medical students are higher than in other student groups. Empathy is an increasingly desired outcome of medical schools. Empathy is negatively associated with burnout in physicians. Our objective was to quantitatively review the available literature on associations between empathy and burnout in medical students, and to explore associations between specific empathy aspects (cognitive and affective) and burnout sub-dimensions (emotional exhaustion, depersonalization and personal accomplishment). METHODS: A comprehensive search of the literature published up until January 2024 was undertaken in the PubMed, EMBASE, CINAHL, The Cochrane Library, and PsycINFO databases. Two independent reviewers screened 498 records and quality-rated and extracted data from eligible studies. The effect size correlations (ESr) were pooled using a random-effects model and between-study variation explored with meta-regression. The review was preregistered with PROSPERO (#CRD42023467670) and reported following the PRISMA guidelines. RESULTS: Twenty-one studies including a total of 27,129 medical students published between 2010 and 2023 were included. Overall, empathy and burnout were negatively and statistically significantly associated (ESr: -0.15, 95%CI [-0.21; -0.10], p < .001). When analyzing sub-dimensions, cognitive empathy was negatively associated with emotional exhaustion (ESr: -0.10, 95%CI [-0.17; -0.03], p = .006) and depersonalization (ESr: -0.15, 95%CI [-0.24; 0.05], p = .003), and positively associated with personal accomplishment (ESr: 0.21, 95%CI [0.12; 0.30], p < .001). Affective empathy was not statistically significantly associated with emotional exhaustion, depersonalization or personal accomplishment. Supplementary Bayesian analysis indicated the strongest evidence for the positive association between cognitive empathy and personal accomplishment. Response rate and gender moderated the relationship so that higher response rates and more male respondents strengthen the negative association between empathy and burnout. CONCLUSION: Greater empathy, in particular cognitive empathy, is associated with lower burnout levels in medical students. This appears to be primarily driven by cognitive empathy's positive association with personal accomplishment. PROTOCOL REGISTRATION: #CRD42023467670.

Frequency of homozygous deletion at p16/CDKN2 in primary human tumours.

Many tumour types have been reported to have deletion of 9p21 (refs 1-6). A candidate target suppressor gene, p16 (p16INK4a/MTS-1/CDKN2), was recently identified within the commonly deleted region in tumour cell lines. An increasing and sometimes conflicting body of data has accumulated regarding the frequency of homozygous deletion and the importance of p16 in primary tumours. We tested 545 primary tumours by microsatellite analysis with existing and newly cloned markers around the p16 locus. We have now found that small homozygous deletions represent the predominant mechanism of inactivation at 9p21 in bladder tumours and are present in other tumour types, including breast and prostate cancer. Moreover, fine mapping of these deletions implicates a 170 kb minimal region that includes p16 and excludes p15.

Is adequate parenting compatible with maternal drug use? A 5-year follow-up.

INTRODUCTION: This prospective, cohort study compares child protection outcomes over the first 5 years of life in a group of children born to self-declared drug-using mothers recruited during pregnancy (cases) and a group of children matched for gestational age, chronological age, maternal neighbourhood and place of delivery whose mothers made no such declaration of problematic drug use (controls). METHODOLOGY: We monitored local child protection registers to identify cohort members who came to the attention of the local authority. RESULTS: Of the 71 original cases and 142 original controls, 55 (77%) and 96 (68%) remained in the area enrolled in local schools at 5 years of age. In total, 26 (47.3%) of the case children were subject to child protection procedures compared with 18 (18.8%) of the control children. This risk difference of 28.5% (95% CI 13.2% to 43.9%) has increased marginally since our previous report in this journal of child protection outcomes at 18 months of age (32% vs. 7%). However, the level of intervention deemed necessary to protect the child has increased significantly with six cases (compared with one control child) taken into the care of the local authority. CONCLUSIONS: Despite early maternal intentions and multiple supportive interventions, 27% of children born to women with significant substance abuse problems in our area required child protection during the pre-school years. Child protection risk assessment procedures need to weigh problematic maternal drug use heavily. Intervention studies with child welfare outcomes are needed to identify the most effective harm reduction strategies and inform public debate on how we can minimize child abuse related to substance misuse.

Methylated DNA sequences for early cancer detection, molecular classification and chemotherapy response prediction.

Molecular studies of many types of cancer have revealed that clinically evident tumours carry multiple genetic and epigenetic abnormalities, including DNA sequence alterations, chromosome copy number changes and aberrant promoter hypermethylation. Together, these aberrant changes result in the activation of oncogenes and inactivation of tumour-suppressor genes (TSG). In many cases these abnormalities can be found in premalignant lesions and even in histological normal adjacent cells. Many tumour types are difficult to detect early and are frequently resistant to available chemotherapy and radiotherapy. Therefore, the early detection, chemoprevention and the design of new therapeutic strategies based on the increased understanding of cancer molecular changes are one of the great challenges nowadays. Insertions of a methyl group at the fifth carbon of cytosines within the dinucleotide 5'- CpG-3' is the best studied epigenetic mechanism. DNA methylation acts together with others mechanisms like histone modification, chromatin remodelling and microRNAs to mould the DNA structure according to the functional state required. The aberrant methylation of the CpG islands located at the promoter region of specific genes is a common and early event involved in cancer development. Thus, hypermethylated DNA sequences from tumours are one of the most promising markers for early detection screenings as well as tumour classification and chemotherapy response in many types of cancer.

Preliminary mapping of the deleted region of chromosome 9 in bladder cancer.

Inactivation of a suppressor gene by deletion of chromosome 9 is a candidate initiating event in bladder carcinogenesis. We have used 13 polymorphic markers spanning the length of chromosome 9 in order to map the region of deletion in human bladder carcinomas. In the majority of tumors loss of heterozygosity was found at all informative sites along the chromosome, indicating deletion of the entire chromosome. Nine tumors had selective deletions of chromosome 9. Mapping of the deleted region in these tumors suggests that the target gene is located between D9S22 at 9q22 and D9S18 at 9p12-13.

Localization of tumor suppressor loci on chromosome 9 in primary human renal cell carcinomas.

To investigate the potential loss of tumor suppressor gene loci on chromosome 9 in human renal cell tumorigenesis we analyzed 42 paired normal and tumor DNAs with 18 polymorphic microsatellite markers spanning this chromosome. Fourteen of 42 (33%) tumors showed partial or complete deletion of chromosome 9. Deletion mapping provided evidence for the presence of a suppressor locus on both the short and long arm of chromosome 9. Homozygous deletion at 9p21-22 in one renal tumor and a selective deletion of distal 9q in another tumor localized the critical regions. The CDKN2/p16 gene was further investigated as a candidate suppressor locus on 9p21-22 by multiplex PCR, Southern analysis, and exon sequencing. We found no additional cases of homozygous deletion nor any rearrangements or point mutations of CDKN2/p16. This is the first report of 9p loss of heterozygosity, homozygous deletion of 9p21-22 and selective deletion of 9q in primary renal cell carcinomas. Understanding the molecular genetic basis of renal cell progression will require the isolation and characterization of additional tumor suppressor genes on chromosome 9.

Homozygous deletions of 9p21 in primary human bladder tumors detected by comparative multiplex polymerase chain reaction.

Deletion mapping studies of primary bladder tumors have identified nonoverlapping areas of loss on each arm of chromosome 9, indicating that two distinct tumor suppressor loci are located on this chromosome. The deleted region on the p arm overlaps an area of 9p previously reported to be lost in a variety of neoplasms. Detailed loss of heterozygosity analysis of 9p in 112 primary bladder tumors using 12 microsatellite markers identified a minimal area of loss around the alpha-interferon locus at 9p21-22. Frequent homozygous deletions of the alpha-interferon locus were then identified in these tumors by a novel, comparative, multiplex polymerase chain reaction assay and were subsequently confirmed by Southern analysis. Based on these deletions, a putative tumor suppressor gene locus involved in bladder tumorigenesis was localized to a 10 cM region (flanked by D9S162 and D9S171), previously implicated in the progression of many neoplasms. Application of the multiplex polymerase chain reaction-based assay will allow rapid identification of homozygous deletions in many neoplasms and thus aid in mapping studies of critical suppressor genes.

Genetic divergence in the clonal evolution of breast cancer.

The progression of ductal carcinoma in situ (DCIS) to infiltrating and metastatic cancer of the breast is thought to be a consequence of clonal expansions of neoplastic cells with progressively more genetic alterations. To study this progression, we first dissected multiple foci from each of 23 breast tumors with DCIS only and 20 cases with synchronous DCIS and infiltrating cancer. We than tested microsatellite markers by PCR for allelic losses in the individual foci for loci on chromosomes 6q, 9p, 11q, 13q, 16q, 17q, and 17p. The patterns of allelic losses identified in the in situ cancers were generally conserved in the synchronous infiltrating tumors, supporting the paradigm that the infiltrating tumors are clonally derived from the in situ lesions. However, in 8 (40%) of the 20 cases with synchronous in situ and invasive cancer, heterogeneous patterns of allelic loss at one or more chromosomal loci were observed in adjacent DCIS foci. Moreover, some of the allelic losses recognized in in situ portions of the tumors were not conserved in the clonal progression to the synchronous invasive tumor. Such allelic loss heterogeneity was noted in only 1 of the 20 infiltrating tumors and only 3 of the 23 cases of DCIS without invasion that were studied in a similar manner. This heterogeneity indicated genetic divergence during the clonal evolution of breast cancer, particularly at the time when in situ cancers progress to invasive cancers.

Partial allelotype of carcinoma in situ of the human bladder.

Carcinoma in situ (CIS) of the urinary bladder is an aggressive lesion that frequently progresses to an invasive tumor, yet the underlying molecular changes in this lesion are largely unknown. In this study, we microdissected 31 cases of CIS and examined them for loss of heterozygosity (LOH) on 13 chromosomal arms. Twenty-nine microsatellite markers were chosen for this analysis based on their location in regions previously shown to be frequently lost in primary transitional cell carcinoma of the bladder. LOH of chromosome 9 was a frequent event in these samples, occurring in 77% of these lesions, with 19 of 31 cases showing deletion on the 9p arm (61%) and 17 of 28 cases displaying LOH on 9q (61%). Fine mapping at 9p21 demonstrated that CIS also displayed a high frequency of homozygous deletion surrounding the p16INK4A locus, like superficial papillary tumors, the other form of noninvasive lesion found in the bladder. However, loss of 14q (70%) was frequent in CIS yet extremely rare in papillary lesions (9%). Other chromosomal arms showing frequent LOH included 8p (65%), 17p (60%), 13q (56%), 11p (54%), and 4q (52%), whereas slightly lower frequencies of loss were observed for 11q (36%), 4p (32%), 3p (31%), 18q (29%), and 5q (20%). CIS lesions already possess many of the genetic alterations displayed by invasive transitional cell carcinomas, potentially accounting for the aggressive nature of these lesions.

Distinct regions of allelic loss on chromosome 4 in human primary bladder carcinoma.

Accumulating evidence implicates the presence of putative tumor suppressor genes on human chromosome 4 that are potentially inactivated in the genesis of several different neoplasms. To accurately determine the frequency of allelic loss on both arms of human chromosome 4, we screened 282 fresh-frozen human bladder carcinomas for allelic loss. Loss of heterozygosity of at least one marker for chromosome 4 was identified in 129 tumors (45.7%). Fine mapping was accomplished using up to 15 polymorphic markers on the p arm and 19 markers on the q arm. We identified a 3-cM minimal area of loss on the p arm between microsatellite markers D4S1608 and D4S404 deleted in 82 tumors (29%). A total of 68 tumors (24%) targeted a 14-cM critical region identified on the distal q arm between markers D4S426 and D4S408. Loss of these two regions correlated with advanced stage and grade of the lesions. These data identify distinct regions of loss on chromosome 4 potentially involved in the late progression of bladder carcinoma.

Novel suppressor loci on chromosome 14q in primary bladder cancer.

Two hundred eighty-five primary human carcinomas of the urinary bladder were examined for allelic loss on chromosome 14q. Seventeen highly polymorphic dinucleotide markers spanning the long arm of this acrocentric chromosome were selected for fine PCR-based mapping. Loss of heterozygosity for at least one marker was observed in 72 (25.3%) tumors. Thirty-four of these 72 tumors (47.2%) lost the entire long arm (monosomy), as suggested by loss of heterozygosity at all informative sites. Allelic loss on 14q occurred in all grades and stages of bladder cancer but was more commonly associated with muscle-invasive tumors (Ta, 9.4%; T1, 24.1%; and > or = T2, 41%). A deletion map of 16 primary tumors with partial losses delineated two minimal regions of loss. One region (approximately 2 cM) was bounded by markers D14S75 and D14S288 and the other (approximately 3 cM) by D14S51 and D14S267. Our results demonstrate that 14q loss is common in invasive bladder cancer and suggest that two potential suppressor loci at 14q12 and 14q32.1-32.2 may contribute to the genetic progression of this common cancer.

Normal polymorphism in the incomplete trinucleotide repeat of the arginine-rich protein gene.

The arginine-rich protein (ARP) gene was recently cloned and localized to human chromosome band 3p21. Recent reports have suggested that ARP is mutated in a high percentage of different human tumors. We amplified and sequenced the multiple arginine coding area of the ARP gene in primary head and neck, non-small cell lung, and renal cell cancers. We found a high frequency of genetic changes in this region, including a single base pair substitution and deletions of arginine repeats in primary tumors. However, these changes were always present in matched normal controls. Thus, the variations in the ARP trinucleotide repeat region represent normal polymorphisms rather than tumor-specific mutations.

High-density mapping of chromosomal arm 1q in renal collecting duct carcinoma: region of minimal deletion at 1q32.1-32.2.

Collecting duct carcinoma (CDC) of the kidney is a rare malignant neoplasm of distal nephron origin. Previous studies of CDC have shown loss of heterozygosity on chromosomal arm 1q in 57% of the cases studied. To better characterize 1q loss in CDC, we performed high-density mapping of the entire long arm of chromosome 1 in 13 CDC tumor samples. We observed complete deletion of chromosomal arm 1q in 5 samples and partial deletion in 4 additional tumors. Our study further showed that the region of minimal deletion is located at 1q32.1-32.2. Sixty-nine percent (9 of 13) of the tumors showed loss of heterozygosity in this area. These data suggest that a gene or group of genes that contribute to the development of distal nephron tumors may be located within the 1q32.1-32.2 region.

Somatic mutations of PTEN in glioblastoma multiforme.

Alterations of the PTEN gene occur in glioblastoma multiforme. To determine the frequency of PTEN alteration, 34 consecutive glioblastomas were studied in detail. Sequencing each of the nine exons amplified from tumor DNA revealed 11 mutations. Analysis of polymorphic markers within and surrounding the PTEN gene identified an additional four homozygous deletion mutations. Loss of heterozygosity (LOH) was observed in 25 of 34 (74%) cases. All mutations occurred in the presence of LOH. PTEN was mutated in 44% (15 of 34) of all glioblastomas studied and 60% (15 of 25) of tumors with LOH on 10q. Thus, PTEN appears to be the major target of inactivation on chromosome 10q in glioblastoma multiforme.

Distal nephron renal tumors: microsatellite allelotype.

Tumors of varying malignant potential arise from the complex epithelial lining of the nephron. Although the molecular characteristics of renal clear cell carcinomas, which arise from the proximal tubule, have been studied, little is known about tumors that develop from other parts of the renal tubular system. To elucidate common molecular lesions that may contribute to the development or progression of nonproximal tubule renal tumors, we performed a detailed microsatellite allelotype of lesions thought to arise from the renal collecting duct. Eighteen collecting duct carcinomas (CDCs) and 13 renal oncocytomas were studied using highly informative microsatellite markers on all autosomal arms. Loss of heterozygosity (LOH) was identified on multiple chromosomal arms in CDCs and renal oncocytomas. Microsatellite analysis revealed LOH of 1q in 57% of informative CDCs. LOH was also observed on arms 6p (45%), 8p (40%), and 21q (40%). In renal oncocytomas, LOH of 1q occurred in approximately 30% of tumors, but 1p LOH was observed in 57% of informative cases analyzed. High levels of LOH were also observed on arms 8p, 14q, 19q, and 21q in the oncocytomas studied. Loss of chromosomal arm 3p was infrequent in both tumor types. Our results suggest that the molecular events that contribute to the development of distal nephron tumors are distinct from those associated with the etiology of proximal tubule renal cancers.

Genomic organization and mutation analysis of Hel-N1 in lung cancers with chromosome 9p21 deletions.

Allelic loss of chromosome 9p21 is common in small cell lung cancer (SCLC), but inactivation of the tumor suppressor gene CDKN2a is rare, implying the existence of another target gene at 9p21. A recent deletion mapping study of chromosome 9p has also identified a site of deletion in non-small cell lung cancer (NSCLC) centered around D9S126. The Hel-N1 (human elav-like neuronal protein 1) gene encodes a neural-specific RNA binding protein that is expressed in SCLC. We have mapped this potentially important gene in lung tumorigenesis to within 100 kb of the D9S126 marker at chromosome band 9p21 by using homozygously deleted tumor cell lines and fluorescence in situ hybridization to normal metaphase spreads. Hel-N1 is, therefore, a candidate target suppressor gene in both SCLC and NSCLC. We have determined the genomic organization and intron/exon boundaries of Hel-N1 and have screened the entire coding region for mutations by sequencing 14 primary SCLCs and cell lines and 21 primary NSCLCs preselected for localized 9p21 deletion or monosomy of chromosome 9. A homozygous deletion including Hel-N1 and CDKN2a was found in a SCLC cell line, and a single-base polymorphism in exon 2 of Hel-N1 was observed in eight tumors. No somatic mutations of Hel-N1 were found in this panel of lung tumors. Hel-N1 does not appear to be a primary inactivation target of 9p21 deletion in lung cancer.

Frequent inactivation of PTEN/MMAC1 in primary prostate cancer.

Sporadic prostate carcinoma is the most common male cancer in the Western world, yet many of the major genetic events involved in the progression of this often fatal cancer remain to be elucidated. Numerous cytogenetic and allelotype studies have reported frequent loss of heterozygosity on chromosomal arm 10q in sporadic prostate cancer. Deletion mapping studies have unambiguously identified a region of chromosome 10q23 to be the minimal area of loss. A new tumor suppressor gene, PTEN/MMAC1, was isolated recently at this region of chromosome 10q23 and found to be inactivated by mutation in three prostate cancer cell lines. We screened 80 prostate tumors by microsatellite analysis and found chromosome 10q23 to be deleted in 23 cases. We then proceeded with sequence analysis of the entire PTEN/MMAC1 coding region and tested for homozygous deletion with new intragenic markers in these 23 cases with 10q23 loss of heterozygosity. The identification of the second mutational event in 10 (43%) tumors establishes PTEN/MMAC1 as a main inactivation target of 10q loss in sporadic prostate cancer.

Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues.

The long arm of chromosome 10 is frequently affected by allelic loss in prostate cancer. PTEN/MMAC1, a candidate tumor suppressor gene located at 10q23.3, a region commonly deleted in prostate cancer, was recently identified and found to be deleted or mutated in cancer cell lines derived from a variety of human tissues including prostate. To examine the role of PTEN/MMAC1 in the progression of prostate cancer, we screened a unique set of 50 metastatic prostate cancer tissues from 19 cancer-death patients for alterations in the PTEN/MMAC1 gene, using single-strand conformational polymorphism analysis and direct sequencing to identify sequence changes and microsatellite analysis to examine allelic loss in the vicinity of PTEN/MMAC1. Overall, gene alterations (deletions or point mutations) were observed in at least 1 metastatic site in 12 of the 19 patients studied. Two cases had homozygous deletions that were confirmed by fluorescence in situ hybridization analysis. Four patients harbored point mutations, with one mutation being found in all four tumors (a primary lesion and three different metastases) from the same patient. The remaining three mutations were detected in only one of multiple metastases. Loss of heterozygosity was found in 10 of 18 informative cases, with 1 case showing a unique pattern of microsatellite instability in each of six different metastases examined. Loss of the same allele was found in all metastases in a given patient in 9 of 10 cases. These results indicate that PTEN/MMAC1 gene alterations occur frequently in lethal prostate cancer, although a substantial amount of mutational heterogeneity is found among different metastatic sites within the same patient. These latter findings emphasize the potentially complex genetic relationship that can exist between various clonal lineages of prostate cancer cells as they evolve during the metastatic process and suggest a molecular basis for phenotypic heterogeneity of different prostate cancer foci in patients with disseminated disease.

High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma.

The tumor suppressor gene p16 (CDKN2/MTS-1/INK4A) can be inactivated by multiple genetic mechanisms. We analyzed 29 invasive primary head and neck squamous cell carcinomas (HNSCC) for p16 inactivation with immunohistochemistry utilizing a new monoclonal antibody (mAb), DCS-50. p16 staining of the primary lesions was correlated with genetic analysis including: (a) detailed microsatellite analysis of markers at the p16 locus to detect homozygous deletion; (b) sequence analysis of p16; and (c) Southern blot analysis to determine the methylation status of the 5' CpG island of p16. Twenty-four of 29 (83%) head and neck squamous cell carcinoma tumors displayed an absence of p16 nuclear staining using immunohistochemistry. Of these 24 tumors, we found that 16 (67%) harbored homozygous deletions, 5 (21%) were methylated, 1 displayed a rearrangement at the p16 locus, and 1 displayed a frameshift mutation in exon 1. These data suggest that: (a) inactivation of the p16 tumor suppressor gene is a frequent event in squamous cell carcinomas of the head and neck; (b) p16 is inactivated by several distinct and exclusive events including homozygous deletion, point mutation, and promoter methylation; and (c) immunohistochemical analysis for expression of the p16 gene product is an accurate and relatively simple method for evaluating p16 gene inactivation.

A region of homozygous deletion on chromosome 9p21-22 in primary nasopharyngeal carcinoma.

Using 21 microsatellite polymorphic markers spanning both p and q arms, we have performed detailed deletion mapping on chromosome 9 in 18 primary nasopharyngeal carcinomas. All 18 tumors were informative at multiple loci. Eleven of the 18 cases (61%) demonstrated allelic deletion of chromosome 9. Among these 11, 6 cases are likely to be tumors with monosomy of chromosome 9. The other 5 cases demonstrated partial deletion by showing multiple areas of allelic loss. In one of the 5 cases, a homozygous deletion region was identified which includes D9S126, D9S171, and IFNA loci at 9p21-22, situated between loci D9S161 (9p21) and D9S162 (9p21-22). The presence of a homozygous deletion strongly suggests the presence of tumor suppressor gene(s) involved in the tumorigenesis of nasopharyngeal carcinoma. The same region has been reported to include some potential tumor suppressor gene loci in other cancers. This is the first reported finding of frequent genetic loss observed on chromosome 9 in nasopharyngeal carcinomas in addition to allelic loss on chromosome 3p at specific regions. Our results suggest that tumorigenesis and progression of nasopharyngeal carcinomas, like other solid tumors, involves multiple genetic changes associated with the inactivation of tumor suppressor genes.