Pandemics of the past: A narrative review.

Infectious diseases resulting in epidemics and pandemics have moulded human history and continue to do so even today. Cholera, plague, human immunodeficiency virus (HIV), and influenza have been some of the most brutal killers. The advancement of medical science has helped us win the war against several of these deadly agents. However, despite all our efforts, new agents continue to emerge. Studying the pandemics of the past helps us respond better to those affecting the globe today. In this narrative review, we present the greatest pandemics of the past, and discuss how the lessons from history may aid us in preparing for the future.

Genotype-based screen for ENU-induced mutations in mouse embryonic stem cells.

The ability to generate mutations is a prerequisite to functional genetic analysis. Despite a long history of using mice as a model system for genetic analysis, the scientific community has not generated a comprehensive collection of multiple alleles for most mouse genes. The chemical mutagen of choice for mouse has been N-ethyl-N-nitrosourea (ENU), an alkylating agent that mainly causes base substitutions in DNA, and therefore allows for recovery of complete and partial loss-, as well as gain-, of-function alleles . Specific locus tests designed to detect recessive mutations showed that ENU is the most efficient mutagen in mouse with an approximate mutation rate of 1 in 1,000 gametes. In fact, several genome-wide and region-specific screens based on phenotypes have been carried out. The anticipation of the completion of the human and mouse genome projects, however, now emphasizes genotype-driven genetics--from sequence to mutants. To take advantage of the mutagenicity of ENU and its ability to create allelic series of mutations, we have developed a complementary approach to generating mutations using mouse embryonic stem (ES) cells. We show that a high mutation frequency can be achieved and that modulating DNA-repair activities can enhance this frequency. The treated cells retain germline competency, thereby rendering this approach applicable for efficient generation of an allelic series of mutations pivotal to a fine-tuned dissection of biological pathways.

Development and Internal Validation of the Postoperative Analgesic Intake Needs Score: A Predictive Model for Post-Operative Narcotic Requirement after Spine Surgery.

STUDY DESIGN: Retrospective Cohort. OBJECTIVE: The aim of this study was to develop a clinical tool to pre-operatively risk-stratify patients undergoing spine surgery based on their likelihood to have high postoperative analgesic requirements. METHODS: A total of 1199 consecutive patients undergoing elective spine surgery over a 2-year period at a single center were included. Patients not requiring inpatient admission, those who received epidural analgesia, those who had two surgeries at separate sites under one anesthesia event, and those with a length of stay greater than 10 days were excluded. The remaining 860 patients were divided into a derivation and validation cohort. Pre-operative factors were collected by review of the electronic medical record. Total postoperative inpatient opioid intake requirements were converted into morphine milligram equivalents to standardize postoperative analgesic requirements. RESULTS: The postoperative analgesic intake needs (PAIN) score was developed after the following predictor variables were identified: age, race, history of depression/anxiety, smoking status, active pre-operative benzodiazepine use and pre-operative opioid use, and surgical type. Patients were risk-stratified based on their score with the high-risk group being more likely to have high opioid consumption postoperatively compared to the moderate and low-risk groups in both the derivation and validation cohorts. CONCLUSION: The PAIN Score is a pre-operative clinical tool for patients undergoing spine surgery to risk stratify them based on their likelihood for high analgesic requirements. The information can be used to individualize a multi-modal analgesic regimen rather than utilizing a "one-size fits all" approach.

Percutaneous screw fixation versus open fusion for the treatment of traumatic thoracolumbar fractures: A retrospective case series of 185 Patients with a single-level spinal column injury.

STUDY DESIGN: Retrospective Single-Center Review of Data at a Level 1 Trauma Center. OBJECTIVE: Compare deformity correction and surgical outcomes of percutaneous instrumentation and open fusion in traumatic thoracolumbar fractures. METHODS: In our retrospective study, all patients undergoing elective spine surgery for TL fractures at a Level 1 trauma center between 2000 and 2017 were reviewed. Patients who underwent percutaneous fixation were given the option of hardware removal after the fracture had healed. RESULTS: A total of 185 patients were included in the study, with 109 treated with an open fusion, and 76 with percutaneous fixation. Twenty-five patients in the latter group had the instrumentation removed after the fracture had healed. None of them required reoperation. In the open fusion group 54.1% of patients required a decompressive laminectomy. Percutaneous fixation patients had a shorter operative time (98.3 min vs 214 min, p < 0.0001), shorter length of stay (9.8 days vs 13.5 days, p = 0.04), and less blood loss (68.4 cc vs 691 cc, p < 0.001). They also had a better correction of their traumatic kyphosis after surgery (p = 0.005). CONCLUSION: Percutaneous fixation is a valuable option for the treatment of TL fractures in cases without evidence of neural compression. It is still unclear whether hardware removal helps prevent adjacent segment degeneration. Percutaneous fixation could allow for better reduction of the fracture with improvement of postoperative alignment.

Early Gestational Diabetes Mellitus: Diagnostic Strategies and Clinical Implications.

Preexisting diabetes mellitus (DM) should be ruled out early in pregnancy in those at risk. During screening, a significant proportion of women do not reach the threshold for overt DM but fulfill the criteria used for diagnosing conventional gestational DM (cGDM). There is no consensus on the management of pregnancies with intermediate levels of hyperglycemia thus diagnosed. We have used the term early gestational DM (eGDM) for this condition and reviewed the currently available literature. Fasting plasma glucose (FPG), oral glucose tolerance test, and glycated hemoglobin (HbA1c) are the commonly employed screening tools in early pregnancy. Observational studies suggest that early pregnancy FPG and Hba1c correlate with the risk of cGDM and adverse perinatal outcomes. However, specific cut-offs, including those proposed by the International Association of the Diabetes and Pregnancy Study Group, do not reliably predict the development of cGDM. Emerging data, though indicate that FPG ≥ 92 mg/dL (5.1 mmol/L), even in the absence of cGDM, signals the risk for perinatal complication. Elevated HbA1c, especially a level ≥ 5.9%, also correlates with the risk of cGDM and worsened outcome. HbA1c as a diagnostic test is however besieged with the usual caveats that occur in pregnancy. The studies that explored the effects of intervention present conflicting results, including a possibility of fetal malnutrition and small-for-date baby in the early treatment group. Diagnostic thresholds and glycemic targets in eGDM may differ, and large multicenter randomized controlled trials are necessary to define the appropriate strategy.

Endocrinology and "Humpty-Dumpty".

Nursery rhymes represent the simplest and most innocent form of performance art. 'Humpty-Dumpty' is a popular character of a nursery rhyme. This character denotes a humanized egg. In medicine, the term 'Humpty-Dumpty syndrome' has been used in many specialities. In neurology, "Humpty-Dumpty" syndrome is used to denote prosopagnosia and in rehabilitation medicine and psychiatry it is used to denote failure of a patient to recover from the psychological trauma of a stressful event in childhood. We believe that the character of "Humpty-Dumpty" potentially represents a patient with Cushing syndrome. In this article we have elaborated the scientific reasons for the same.

Takotsubo Endocrinopathy.

Takotsubo cardiomyopathy (TCMP) is a cardiac disorder, often seen in post-menopausal women, that resembles an acute coronary syndrome in its clinical presentation. The aetiopathogenesis of TCMP may have an endocrine basis, and hence we believe the term 'takotsubo endocrinopathy' may be more appropriate. In this review, we describe the various endocrine disorders that may lead to TCMP. We also describe the pathogenetic mechanism by which these endocrine disorders may lead to TCMP. Cardiomyopathy associated with pheochromocytoma closely resembles TCMP and we have suggested that it must be ruled out in all patients presenting with TCMP. The role of oestrogen deficiency in the pathogenesis of TCMP is examined in this article. The importance of the involvement of an endocrinologist in the management of TCMP is emphasised.

Tumoral Mimics of Subdural Hematomas: Case Report and Review of Diagnostic and Management Strategies in Primary B-Cell Lymphoma of the Subdural Space.

BACKGROUND: Subdural lymphomas are a rare subtype of primary central nervous system lymphomas that can radiographically mimic epidural blood and pose a diagnostic challenge. They can complicate treatment if not preemptively identified. METHODS: We present a case report of a subdural lymphoma that mimicked a compressive subdural hematoma, and we review the PubMed database for similar cases. RESULTS: A 77-year-old woman presented with a transient left facial droop and what appeared to be a subdural hematoma on computed tomography scan. The patient underwent surgery, during which grossly abnormal solid epicortical adherent tissue was noted instead of the expected appearance of a subdural hematoma. An intraoperative biopsy was suggestive of lymphoma, and the surgery was converted to a craniectomy. Pathology confirmed the diagnosis of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The patient underwent radiotherapy with no complications or recurrence. Magnetic resonance imaging demonstrated complete resolution of the mass at 3 months after treatment, at which time the patient underwent a synthetic cranioplasty. Seven case reports of primary dural lymphomas mimicking subdural blood were found, with variable pathologic subclassifications. CONCLUSIONS: Although rare, a primary dural lymphoma can be mistaken for a subdural hematoma on computed tomography scan. The most common subtype is low-grade extranodal marginal zone lymphomas. It is important to keep these diseases in the differential diagnosis, especially when there is incongruence between imaging and the clinical picture, as earlier detection correlates to a stronger therapeutic response.

Extraneural metastatic anaplastic ependymoma: a systematic review and a report of metastases to bilateral parotid glands.

BACKGROUND: Anaplastic ependymoma with extraneural metastases is associated with a poor clinical outcome. Metastatic spread to the parotid gland is a rare clinical entity that requires multidisciplinary intervention. Herein, we present a systematic review of anaplastic ependymoma with extraneural metastases and report on a case with metastases to both parotid glands. METHODS: Electronic databases were searched from their inception to February 2019. Inclusion criteria included reports of anaplastic ependymoma with extraneural metastasis. Studies were excluded if the tumor grade was not reported. A case illustration is provided. RESULTS: The search yielded 15 cases of anaplastic ependymoma with extraneural metastases, including the present case. Mean age at diagnosis was 15 years. The initial tumor location was predominantly supratentorial (93.3%). All cases demonstrated leptomeningeal seeding before extraneural metastasis. Mean survival from initial diagnosis was 4.5 years. Metastasis to the parotid gland occurred in 2 cases, including the present case. We present a 17-year-old female patient who underwent gross total resection of a supratentorial, paraventricular anaplastic ependymoma followed by adjuvant external beam radiation therapy. The patient developed recurrent leptomeningeal seeding, treated with Gamma Knife radiosurgery over a 5-year period. She returned with a parotid mass and cervical lymphadenopathy and underwent parotidectomy and modified radical neck dissection. She continued to experience recurrences, including the left parotid gland, and was ultimately placed in hospice care. CONCLUSIONS: Anaplastic ependymoma with extraneural metastasis is rare. A combination of repeated surgical resection, radiation therapy, and chemotherapy can be used to manage recurrent and metastatic disease, but outcomes remain poor.

Oculomotor Schwannomas: A Systematic Review and Report of Two Pediatric Cases Treated with Fractionated Cyberknife Stereotactic Radiotherapy.

OBJECTIVE: Pediatric oculomotor nerve schwannomas are rare and challenging lesions due to the high morbidity associated with surgical intervention and their proximity to critical structures limiting the opportunity for stereotactic radiosurgery. We aim to report and review the novel use of fractionated Cyberknife (Accuray, Inc., Sunnyvale, California, USA) stereotactic radiotherapy in pediatric patients with oculomotor schwannomas. METHODS: A systematic review of PubMed, Embase, and Cochrane was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two patients, ages 8 and 10 years, with tumor volumes of 0.1 cm3 and 0.2 cm3, respectively, were treated with fractionated Cyberknife radiotherapy at our institution. A total dose of 45-50 Gy was administered over 25 fractions (1.8-2.0 Gy per fraction) to the 82%-84% isodose line. Serial magnetic resonance imaging was obtained for long-term follow-up (56-58 months). RESULTS: We found 14 articles published between 1982 and 2018 that reported a total of 18 pediatric patients with intracranial oculomotor schwannomas. No previously described cases of pediatric intracranial oculomotor schwannomas were treated with radiation therapy. In both of our patients, radiographic tumor control was achieved at a mean follow-up of 57 months, with 1 patient displaying a decrease in tumor volume. Neither patient exhibited any worsening of their presenting symptoms, nor did either patient develop any new neurocognitive deficits following treatment. CONCLUSIONS: Fractionated Cyberknife radiotherapy is an effective and well-tolerated treatment option for intracranial oculomotor nerve schwannomas with excellent tumor control rates, similar to surgical and radiosurgical techniques, while sparing critical surrounding structures.

Lumbar drain trial outcomes of normal pressure hydrocephalus: a single-center experience of 254 patients.

OBJECTIVE: A short-term lumbar drain (LD) trial is commonly used to assess the response of normal pressure hydrocephalus (NPH) patients to CSF diversion. However, it remains unknown whether the predictors of passing an LD trial match the predictors of improvement after ventriculoperitoneal shunting. The aim of this study was to examine outcomes, complication rates, and associations between predictors and outcomes after an LD trial in patients with NPH. METHODS: The authors retrospectively reviewed the records of 254 patients with probable NPH who underwent an LD trial between March 2008 and September 2017. Multivariate regression models were constructed to examine predictors of passing the LD trial. Complications associated with the LD trial procedure were recorded. RESULTS: The mean patient age was 77 years and 56.7% were male. The mean durations of gait disturbance, cognitive decline, and urinary incontinence were 29 months, 32 months, and 28 months, respectively. Of the 254 patients, 30% and 16% reported objective and subjective improvement after the LD trial, respectively. Complications included a sheared LD catheter, meningitis, lumbar epidural abscess, CSF leak at insertion site, transient lower extremity numbness, slurred speech, refractory headaches, and hyponatremia. Multivariate analyses using MAX-R revealed that a prior history of stroke predicted worse outcomes, while disproportionate subarachnoid spaces (uneven enlargement of supratentorial spaces) predicted better outcomes after the LD trial (r2 = 0.12, p < 0.05). CONCLUSIONS: The LD trial is generally safe and well tolerated. The best predictors of passing the LD trial include a negative history of stroke and having disproportionate subarachnoid spaces.

Clinical outcomes of normal pressure hydrocephalus in 116 patients: objective versus subjective assessment.

OBJECTIVE: Objective assessment tests are commonly used to predict the response to ventriculoperitoneal (VP) shunting in patients with normal pressure hydrocephalus (NPH). Whether subjective reports of improvement after a lumbar drain (LD) trial can predict response to VP shunting remains controversial. The goal in this study was to compare clinical characteristics, complication rates, and shunt outcomes of objective and subjective LD responders who underwent VP shunt placement. METHODS: This was a retrospective review of patients with NPH who underwent VP shunt placement after clinical improvement with the LD trial. Patients who responded after the LD trial were subclassified into objective LD responders and subjective LD responders. Clinical characteristics, complication rates, and shunt outcomes between the 2 groups were compared with chi-square test of independence and t-test. RESULTS: A total of 116 patients received a VP shunt; 75 were objective LD responders and 41 were subjective LD responders. There was no statistically significant difference in patient characteristics between the 2 groups, except for a shorter length of stay after LD trial seen with subjective responders. The complication rates after LD trial and VP shunting were not significantly different between the 2 groups. Similarly, there was no significant difference in shunt response between objective and subjective LD responders. The mean duration of follow-up was 1.73 years. CONCLUSIONS: Reports of subjective improvement after LD trial in patients with NPH can be a reliable predictor of shunt response. The currently used objective assessment scales may not be sensitive enough to detect subtle changes in symptomatology after LD trial.

Correlation between Basal Insulin Glargine Dose Required in Achieving Target Fasting Blood Glucose and Various Clinical and Laboratory Parameters in Hospitalized Noncritical Patients.

AIMS: The primary objective was to study the interrelationship between the basal insulin glargine dose and baseline clinical and laboratory parameters in noncritically ill hospitalized patients who have achieved the stable fasting blood glucose in the target range of 100-140 mg/dl. PATIENTS AND METHODS: This was retrospective, cross-sectional, observational study. Consenting, nonpregnant, adult patients on basal-bolus insulin who had fasting capillary blood glucose in the range of 100-140 mg/dl as measured by glucometer for 3 consecutive days were included in this study. Patient receiving any basal insulin other than insulin glargine were excluded from this study. The data collected for these patients included age, sex, glycated hemoglobin (HBA1c) at the time of admission, timing of basal insulin, basal insulin dose (BID), BID/kg, weight, and serum creatinine. BID/kg was correlated with other parameters using regression analysis (Pearson's). Comparison of BID/kg in various subgroups was analyzed using Student's t- test. Parametric data of more than three groups were compared using ANOVA. The P < 0.05 was considered as statistically significant. RESULTS: A total of 180 patients were included in the study. On correlating the BID/kg with various parameters, we found statistically significant correlation between BID/kg and glycated hemoglobin (HbA1c) at the time of admission (P = 0.044). Patients with HbA1c ≥8.0% had higher BID/kg compared to those with HbA1c <8.0% (P = 0.004). The mean BID in patients with renal failure was significantly higher compared to those without renal failure. CONCLUSION: HbA1c at the time of admission is the most important parameter for determining the appropriate BID in hospitalized patients. Patients with renal failure may require a higher dose of basal insulin than those not having renal failure.

Management of Primary Adrenal Insufficiency: Review of Current Clinical Practice in a Developed and a Developing Country.

Treatment of primary adrenal insufficiency (PAI) requires lifelong hormone replacement with glucocorticoids (GCs) and mineralocorticoids. Impaired quality of life and increased standardized mortality ratio in these patients emphasize the importance of tailoring therapy to individual needs. Role of education is paramount in improving patient compliance and in anticipating and preventing adrenal crises. Although discovery of synthetic GCs was a major breakthrough in treatment of patients with this life-threatening condition, management of PAI continues to be challenging. The obstacles for clinicians appear to vary widely across the globe. While optimization and individualization of therapy after diagnosis of PAI remain the main challenges for clinicians in the developed world, doctors in a developing country face problems at almost every stage from the diagnosis to the treatment and follow-up of these patients; cost of therapy, lack of resources, and funding are the main hindrances. Adherence to therapy and patient education are found to be common issues in most parts of the world. This commentary highlights the challenges from both developed and developing country's perspective in treating PAI; it also provides an update on current management scenario and future treatment options.

Comparison of Two Protocols in the Management of Glucocorticoid-induced Hyperglycemia among Hospitalized Patients.

CONTEXT: There is limited literature focusing on the management of glucocorticoid-induced hyperglycemia (GCIH). AIMS: The primary objective was to compare the mean blood glucose between the experimental group (new protocol) and the control group (standard protocol) in the management of GCIH. The secondary objective was to compare other parameters of glycemic efficacy, variability, and safety parameters. METHODS: This was a randomized, open-labeled, parallel arm trial. Adult patients who were given glucocorticoid (minimum dose equivalent to prednisolone 10 mg) in the past 24 h and had 2 h postmeal plasma glucose ≥200 mg/dl were included in the study. Patients randomized to control group received standard basal-bolus insulin. In the experimental group, a "correctional insulin" matching the glycemic profile of the glucocorticoid administered was provided with or without "background" basal-bolus insulin. The parameters of glycemic efficacy, variability, and safety were compared. P < 0.05 was considered statistically significant. RESULTS: Data of 67 patients included in the study were analyzed, of which 33 patients were in the experimental group and 34 patients in the control group. The mean blood glucose in the experimental and the control group was 170.32 ± 33.46 mg/dl and 221.05 ± 49.72, respectively (P = 0.0001). The parameters for glycemic variability were all significantly lower in patients in the experimental group. The hypoglycemia event rate was low in both the groups. CONCLUSION: When compared to the standard basal-bolus insulin protocol, the new protocol showed lower mean blood glucose and lower glycemic variability.

Kumbhakarna: Did he suffer from the disorder of the hypothalamus?

Kumbhakarna was brother of the evil Raavana in the mythological tale of Ramayana. According the legend, Kumbhakarna had an insatiable appetite and thirst and used to sleep for great lengths of time. He also had an uncontrollable temper, which was feared by many. It is our assessment that Kumbhakarna possibly suffered from hypothalamic obesity. Hypothalamic obesity can be defined as significant polyphagia and weight gain that occurs because of structural or function involvement of the ventromedial nucleus of the hypothalamus bilaterally. The characteristic features are obesity associated with polyphagia. Somnolence is present in 40% of cases. Sham rage is a characteristic behavioral abnormality seen in these patients. All these symptoms are described in the mythological text while describing Kumbhakarna. The episodic nature of Kumbhakarna's symptoms can also be explained by another hypothalamic syndrome called Klein-Levine syndrome. This syndrome is characterized by with periodic episodes of somnolence, hyperphagia and hypersexuality along with other behavioral and cognitive difficulties.

Short stature with congenital ichthyosis.

PIBIDS syndrome (photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility and short stature) is a variant of trichothiodystrophy. It is a rare form of autosomal recessive congenital ichthyosis. Short stature is a vital component of PIBIDS syndrome. We present the cases of two siblings in whom we diagnosed PIBIDS syndrome. On evaluation for short stature, they were found to have severe vitamin D deficiency, which on correction led to the patients having considerable gain in stature. With this case, we would also like to propose that vitamin D deficiency could be one of the treatable causes of short stature in PIBIDS syndrome.